Download Bleeding Disorders

Bleeding Disorders
Jaya V Juturi, MD
Texas Oncology, PA
HEMOSTASIS
Regulating factors
 Vessel Wall Integrity
 Adequate Numbers of Platelets
 Proper Functioning Platelets
 Adequate Levels of Clotting Factors
 Proper Function of Fibrinolytic Pathway
HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
VASCULAR PHASE
WHEN A BLOOD VESSEL IS
DAMAGED, VASOCONSTRICTION
RESULTS.
Vascular wall ( Endothelium)

Antithrombotic properties
– Antiplatelet effects
– Anticoagulant properties
– Fibrinolytic properties

Prothrombotic properties
– Von Willebrand factor
– Tissue factor
– Fibrinolysis inhibitors
HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
PLATELET PHASE
PLATELET PHASE
Glanzmann’s
Platelet Activation Mechanisms
From Henry’s Clinical Diagnosis and Management by Laboratory Methods, McPherson and Pincus, eds, Saunders Elsevier, 2006.
Platelet Plug

Initial hemostatic response at the site of injury

Adhesion – deposition of platelets on the subendothelial matrix with
vWf. (GP Ib)

Aggregation – platelet-platelet cohesion with GP IIb/IIIa (ADP
mediated, calcium facilitated)

Secretion – release of granule proteins

Procoagulant – enhancement of thrombin generation

PLATELETS ADHERE TO THE DAMAGED SURFACE AND FORM
A TEMPORARY PLUG.
HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
COAGULATION PHASE
THROUGH TWO SEPARATE PATHWAYS
THE CONVERSION OF FIBRINOGEN TO
FIBRIN IS COMPLETE.
THE CLOTTING MECHANISM
INTRINSIC
EXTRINSIC
Tissue
Thromboplastin
Collagen
XII
XI
VII
IX
VIII
X
V
PROTHROMBIN
(II)
THROMBIN
(III)
FIBRINOGEN (I)
FIBRIN
Coagulation cascade
Intrinsic system (surface contact)
Extrinsic system (tissue damage)
XIIa
XII
Tissue factor
XIa
XI
IX
IXa
VIII
VIIa
VII
VIIIa
X
Xa
V
Va
II
Fibrinogen
Vitamin K dependant factors
IIa (Thrombin)
Fibrin
Factors produced in the liver







Prothrombin
Factor V
Factor VII
Factor IX
Factor X
Fibrinogen
AT III
Factor XI
Factor XII
Prekallikrein
HMWK
Factor XIII
Protein C
HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE
ACTIVATED TO ALLOW CLOT
DISINTEGRATION AND REPAIR OF
THE DAMAGED VESSEL.
Approach to a bleeding disorder

History
–
–
–
–
–
Very important
Duration of symptoms
When do they occur
Prior trauma/surgery
Other medical
conditions
– Family history

Medication usage

Examination
– Petechiae
– Ecchymosis

Labs
–
–
–
–
–
–
CBC with smear
PT
PTT
Thrombin time
Fibrinogen
Platelet function assay
REVIEW PATIENT’S MEDS
FIVE DRUGS THAT INTERFERE WITH
HEMOSTASIS
 ASPIRIN
 ANTICOAGULANTS
 ANTIBIOTICS
 ALCOHOL
 ANTICANCER
Diagnosis of Bleeding Disorder
History
Neonatal bleeding
Bleeding after circumscision
Delayed bleeding from umbilical stump (factor XIII)
Deep hamatoma after IM injections
Epistaxis
Dental extraction, tonsils, adenoids
Site of bleeding: skin, mucous membranes, joints
Family history of bleeding disorders
Drug exposure
The presence of conditions causing bleeding: SLE, nephrosis,
hypothyroidism, Ehler Danlos
Primary Vs Secondary Defect:
Clinical Manifestations
Normal Peripheral Smear
Platelet lumiaggregation:
Examples of
Normal and of
Glanzmann
Thrombasthenia
From Henry’s Clinical Diagnosis and Management by Laboratory Methods, McPherson and Pincus, eds, Saunders Elsevier, 2006.
Overview of Common Coagulation Tests
From Henry’s Clinical
Diagnosis and Management
by Laboratory Methods,
McPherson and Pincus, eds,
Saunders Elsevier, 2006.
Petechiae
Do not blanch with
pressure, Not palpable
ORAL MANIFESTATIONS

Petechiae & Ecchymosis
 Gingival Hyperplasia
 Spontaneous Gingival Bleeding
 Ulceration of Oral Mucosa
 Lymphadenopathy
Figure 1. This picture demonstrates petechiae in dependent areas of a thrombocytopenic
patient with AML
Maslak, P. ASH Image Bank 2008;2008:8-00089
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
LABORATORY EVALUATION
 PLATELET COUNT
 PROTHROMBIN TIME (PT)
 PARTIAL THROMBOPLASTIN TIME (PTT)
 THROMBIN TIME (TT)
 FIBRINOGEN
Figure 1. Review of the peripheral smear reveals a paucity of platelets
Maslak, P. ASH Image Bank 2004;2004:101214
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
THROMBIN TIME
 Time for Thrombin To Convert
Fibrinogen
Fibrin
 A Measure of Fibrinolytic Pathway
NORMAL VALUE
9-13 SECS
Initial Evaluation of a Bleeding Patient - 1
Normal PT
Normal PTT
Urea
solubility
Abnormal
Factor XIII
deficiency
Normal
Consider evaluating for:
Mild factor deficiency
Monoclonal gammopathy
Abnormal fibrinolysis
Platelet disorder
(a2 anti-plasmin def) Vascular disorder
Elevated FDPs
Normal PT
Abnormal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific (anti-phospholipid Ab)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway (factors VIII, IX, XI)
Multiple factor deficiencies (rare)
Initial Evaluation of a Bleeding Patient - 3
Abnormal PT
Normal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific: Anti-phospholipid (rare)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency of factor VII (rare)
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
Initial Evaluation of a Bleeding Patient - 4
Abnormal PT
Abnormal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin,
fibrinogen (rare)
Non-specific: anti-phospholipid (common)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in common pathway: Factors V, X,
Prothrombin, Fibrinogen
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
Coagulation factor deficiencies
Summary
Sex-linked recessive
 Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal
Autosomal recessive (rare)
 Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT
 Factor XIII deficiency is associated with bleeding and
impaired wound healing
PT/ PTT normal; clot solubility abnormal
 Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding
Pathology
Bleeding
disorders
Vascular
abnormalities
Platelet disorders
Clotting factor
abnormalities
DIC
Vascular abnormalities

Causes
– Infections
 Meningococcemia, Rickettsioses , Infective endocarditis
– Drug reactions
– Hereditary hemorrhagic telangiectasia
 Autosomal dominant
– Cushing syndrome
– Henoch - Schönlein Purpura
 systemic hypersensitivity disease of unknown cause
 polyarthralgia, and acute Glomerulonephritis
 Palpable purpuric rash, colicky abdominal pain
– Scurvy and the Ehlers-Danlos syndrome
– Amyloid infiltration of blood vessels
Bleeding
disorders
Vascular
abnormalities
***
Platelet disorders
Clotting factor
abnormalities
DIC
Bleeding disorders
Platelet disorders
↓production
↑destruction
Primary/Idiopathic
ITP
Acute/Chronic
Sequestration
Hypersplenism
Secondary
Drugs, HIV
Immune Thrombocytopenic
Purpura (ITP)

Cause
– Antiplatelet antibodies
– Antigen - platelet membrane glycoprotein complexes IIb-IIIa
and Ib-IX
 Morphology
– Peripheral Blood
 thrombocytopenia, abnormally large platelets (megathrombocytes
or Giant platelets),
– Marrow
 Normal or Increased magakaryocyte #

Diagnosis - by exclusion, normal PT and PTT
Diagnosis
Exclude other causes
 Evaluate for other syndromes

– SLE
– APS
– Lymphomas
– HIV

Look at peripheral blood smear
– Pseudothrombocytopenia, hemolysis, large
platelets
ITP
Feature
Acute
Chronic
Age / Sex
Children
Adult/Female
Onset
Abrupt
Gradual
Predisposing
Factors
Viral infection/
vaccine
-
Duration
<2 months
>6mnoths
Pathogenesis
-
IgG against Platelet
GP
Same
Peripheral smear Thrombocytopenia
& Giant PLTS
Bone marrow
Normal or
↑Megakaryocytes
Same
ITP
Feature
Acute
Chronic
Tests
Normal PT & PTT
Same
Complication
Intracranial bleed
(most dangerous)
Same
Clinical course
Spontaneous
remission
No
If <20,000
No
If <50,000
Yes (refractory
cases)
Treatment
 PLT.
Transfusion/treat
 Splenectomy
Treatment
No need to treat if platelet count above
20-30k.
 Initial therapy

– Prednisone 1 mg/kg divided bid
– Decadron 40 mg daily x 4 days
– High dose solumedrol
 May increase platelet count faster
 More side effects
– IVIG for serious presentation
Treatment


50% relapse after initial therapy or remain steroid dependent
Splenectomy especially for steroid responsive cases
– 80% response rate
– Immunize prior







Anti-D immune globulin in Rh+ patients
Rituxan
Danazol
Dapsone
Vincristine
Immunosuppression with azathioprine, cytoxan
Thrombopoietan receptor agonists – Nplate and Promacta
– ?rebound worsening when drugs stopped
– Myelofibrosis
Drug induced thrombocytopenia
Heparin induced thrombocytopenia (HIT)





Seen in 3-5% of patients treated with unfractionated
heparin
thrombocytopenic after 1-2 weeks of Rx
Caused by IgG antibodies against platelet factor
4/heparin complexes on platelet surfaces
Exacerbates thrombosis, both arterial and venous (in
setting of severe thrombocytopenia)
– Antibody binding results in platelet activation and
aggregation.
Rx - cessation of heparin
Other drugs???
Thrombotic Microangiopathies
1.
2.
Thrombotic thrombocytopenic Purpura (TTP)
Hemolytic-Uremic syndrome (HUS)
Thrombotic Microangiopathies
common for both disorders



Mechanism =***hyaline (platelets) thrombi in the
microcirculation
Pathogenesis = Systemic endothelial cell damage
Clinically = Fever, Thrombocytopenia, Renal failure,
Hemolytic anemia, neurological symptoms
***How to differentiate them from DIC?
HEMOLYSIS/HEMOLYTIC ANEMIAS
DUE TO RBC TRAUMA
Mechanical heart valves
breaking RBC’s
 MICROANGIOPATHIES:
– TTP
– Hemolytic Uremic Syndrome

Schistocytes: Microangiopathic
Hemolytic Anemia
Thrombotic Microangiopathies
HUS
Feature
TTP
Absent
Neurological
symptoms
Prominent
Prominent
Acute Renal Failure
Less prominent
Children
Age
Adults
Infection
( E.coli O157 : H7)
Cause
Genetic
(vWF
metalloproteaseADAMTS 13)
deficiency
Supportive
Rx.
Plasma Exchange
Good in children
Bad in adults
Prognosis
Better with plasma
exchange
Mechanisms of thrombocytopenia and anemia in TTP:
Comparison with the normal physiological state
In the absence of ADAMTS13 (or when the concentrations of ADAMTS13 are
not sufficient to cleave the increased quantity of UL VWF multimers released by
the activated endothelial cells), UL VWF aggregates the platelets within the
vessels causing thrombi that block blood flow. The red cells passing through
the thrombi become fragmented and form schistocytes.
Mannucci PM. Pathophysiol Haemost Thromb. 2006;35(1-2):89-97. Thrombotic
thromboytopenic purpura: another example of immunomediated thrombosis.
Platelet functional disorders
Figure 1. Lumiaggregometry tracing demonstrates simultaneous platelet aggregation (red
and blue curves) and ATP release (green and black curves) in response to collagen used as
an agonist
Maslak, P. et al. ASH Image Bank 2009;2009:9-00008
Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Bleeding
disorders
Vascular
abnormalities
Platelet disorders
Clotting factor
abnormalities
DIC
Clotting factor abnormalities

Congenital disorders
– Von Willebrand disease –MC with minimal bleeding
– Factor VIII Deficiency - Hemophilia A or Classic Type
– Factor IX Deficiency – Hemophilia B

Acquired disorders
– Vit. K deficiency =Due to deficient carboxylation of factors II,
VII, IX &X
– Oral anti-coagulants
 Coumarin derivatives= warfarin – inhibit Vit. K factors
 Liver diseases ↓ synthesis of factors
Von Willebrand Disease






MC inherited bleeding disorder with mild bleeding
Autosomal dominant
TYPE I =Most common (70% of all cases)
Prolonged bleeding time but normal platelet count
↓Plasma vWF levels
Secondary ↓ in Factor VIII levels
von Willebrand Disease
Clinical features

von Willebrand factor Carrier of factor VIII anchors
platelets to subendothelium Bridge between platelets

Inheritance
Autosomal dominant

Incidence
1/10,000

Clinical features
Mucocutaneous bleeding
Effect of blood group on plasma
vWF level
Blood group
O
A
B
AB
Plasma vWF level
U/dI
75
106
117
123
Treatment of von Willebrand disease
Varies by Classification

Cryoprecipitate
– Source of fibrinogen, factor VIII and VWF
– Only plasma fraction that consistently contains VWF multimers
– Correction of bleeding time is variable

DDAVP (Deamino-8-arginine vasopressin)
– Increases plasma VWF levels by stimulating secretion from
endothelium
– Duration of response is variable
– Used for type 1 disease
– Dosage 0.3 µg/kg q 12 hr IV

Factor VIII concentrate (Humate-P)
– Virally inactivated product
– Used for type 2 and 3
***Hemophilia A

MC hereditary disease with serious bleeding
– X-linked recessive
– In 30% No family history (new mutations)
– 15% of severe cases develop factor VIII inhibitors

↓ amount or activity of factor VIII

factor VIII = cofactor for activation of factor X in the coagulation
cascade

Symptoms usually develop in severe cases (factor VIII <1% of
normal) – hemoarthrosis, bruising, hemorrhage after trauma or
surgery
Hemophilia B

Factor IX deficiency

X-linked recessive

Much less common

Clinically= indistinguishable from Hemophilia A with Similar
lab findings

Diagnosis by factor IX levels

Treat with recombinant IX
Hemophilia
X-linked disorder
 Factor VIII or IX
 Females carriers
Mild
Moderate
Severe
Factor
level
>5%
1-5%
<1%
Bleeding
Rare
3-4x/year
Multiple
Treatment
Supportive
Supportive
prophylaxis

– Symptoms

New mutation
– 30%
– VIII gene huge
Infectious risks
 Hemarthropathy

Acquired Hemophilia






Occurs in malignancy, autoimmune disorders,
post-partum
PTT prolonged
Mixing studies – immediate and delayed
Bethesda assay – measurement of strength of
the inhibitor
Treatment is with alternative factor concentrates
Immunosuppression to clear inhibitor
Fresh Frozen Plasma

Advantages:
• Availability.

Disadvantages:
• Volume problems
• Infectious exosure: hep. C, HIV, hep. B
• Clotting activity by freezing and thawing (-15%)

Indications:
• Deficiency of factors V, VII, IX, X and XIII
• Multiple deficiencies: servere liver disease and DIC.
• Unknown cause.
Cryoprecipitate
Prepared form single units of donor plasma.
Contains 50% of VIII C, vW activity, fibrinogen, XIII.
= 100 units of factors vIII C.
Main uses:
 Treatment of choice of VW disease except type 1.
 Hemophilia A, Hypo & dysfibrinogenemia.
Disadvantages:
 Should be kept at deep freeze (-20 to -30 C).
 Difficult to handle at home.
 Cryoprecipitate vary in factor VIII C content from bag to bag.
Dosages: similar to factor VIII
1 bag 100 units
Commercially Prepared Factor VIII
Concentrates
Advantages:
 Easy storage, reconstitution and infusion.
 Each bottle contains a fixed amount of
factor VIII.
 No volume problem.
Disadvantages:
 Infectious exposure HIV.
 Hep C. Hep B and others.
Prothrombin complex concentrates
Contains: vit. K dependent factors + protein C.
Activated factors: hemophilia A & B.
Uses:
 Hemophilia B.
 Hemophilia A with inhibitors.
Advantages:
 Easy to store (-4C) and to administer.
Main problems:
 Infection risk.
 DIC and thromboembolic phenomena.
 Thromboembolic phenomena, this risk increase in:
– Injury & high tissue thrompoblastin activity.
– Liver disease because of low levels of antithrombin III.
– Neonates.
Recombinant concentrates
Factors VII, VIII, IX
Effective in clinical trials
Advantages
 No infectious risk.
 No volume problems.
Bleeding
disorders
Vascular
abnormalities
Platelet disorders
Clotting factor
abnormalities
DIC
Disseminated Intravascular Coagulation

Characterized by =activation of the coagulation sequence systemic microthrombi

Sequelae= tissue hypoxia due to microinfarcts (Thrombotic) or bleeding
problems

Triggering Pathways
– Release of tissue factor / thromboplastic factors into circulation
– Widespread endothelial injury

Mechanism=Activated monocytes release IL-1 and TNF α ↑ expression of
tissue Thromboplastic factor on endothelial cells & decrease Thrombomodulin
– Mechanism = Consumption of coagulation factors , platelets, and activation
of fibrinolytic pathways
Disseminated Intravascular Coagulation
contd…


Sources of thromboplastic substances:
– Leukemic cell granules
– Placenta in obstetric complications
– Carcinomas- (Mucin - secreting adenocarcinomas)
– Bacterial endo and exotoxins
Endothelial injury can also be Caused by
– Antigen-antibody complexes =S.L.E.
– Temperature extremes= Heat stroke or burns
– Microorganisms=Rickettsae, meningococci
Disseminated Intravascular Coagulation
contd…
Plasmin Fibrinolysis  formation of fibrin degradation products
(FDP)
– D-Dimer most important of FDPs
 Organ damage due to Micro thrombi
– Kidney =microinfarcts in the renal cortex
 In severe cases = bilateral renal cortical necrosis
– Adrenals = bilateral adrenal hemorrhage
 resembles waterhouse - Friderichsen syndrome
– Brain= Microinfarcts surrounded by foci of hemorrhage
– Heart and anterior pituitary= show Similar changes

Disseminated Intravascular Coagulation
contd…

Clinically= Bleeding tendency in presence of widespread
coagulation
– Acute D.I.C.= dominated by a bleeding
 seen in obstetrical complications and trauma
– Chronic D.I.C.= presents with Thrombotic complications
 seen in cancers
 Manifestations = variable
– Minimal to profound shock, renal failure, dyspnea, cyanosis,
convulsions, and coma
– Hypotension is characteristic.

Disseminated Intravascular Coagulation
contd…

Lab = PT And PTT Are typically prolonged.
– Thrombocytopenia
– low Fibrinogen
– Elevated plasma Fibrin split products
 Prognosis = Highly variable
– Depends upon:
 Underlying disorder
 Degree of intravascular clotting
 Activity of mononuclear phagocytic system
 Amount of Fibrinolysis

Treatment of the underlying disorder is most important!!
How to differentiate DIC form HUS/TTP using lab parameters?
ALL
CLL
Antithrombin III concentrate
Neutralizes mainly thrombin.
 Inhibits activated factor xa.
Also factor IXa, XIa, XIIa.
 Uses:

1. Congenital deficiency states acute
thrombosis.
2. Congenital deficiency states before surgery.
3. Acquired deficiency states thrombosis or
DIC.
Antifibrinolytic therapy
Effective in controlling mucosal bleeding especially the
oral mucosa (prevent rebleeds)
Not well studied for: nasal, urinary and GIT bleeding
EACA (Amicar) 500 mg tab, 250/mL elixir
Dose 100-200 mg/Kg (maximum 10 g initial)
50-100 mg/kg/dose (max 5 g) every 6 hours
Transexamic acid (cyclockapron) 500mg cap.
25 mg/kg/dose every 6 hours
tranexamic acid effective locally as mouth wash