BLEEDING DISORDERS

Dr Alex Mogere
Consultant Physician
 HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
 Lab Tests
Hemostasis •CBC-Plt
•BT,(CT)
BV Injury •PT
Tissue Factor •PTT
Neural

Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation
Plt Study
Morphology
Stable Hemostatic Plug Function
Antibody
NORMAL CLOTTING
Response to vessel injury
1. Vasoconstriction to reduce blood flow
2. Platelet plug formation (von willebrand factor binds
damaged vessel and platelets)
3. Activation of clotting cascade with generation of fibrin
clot formation
4. Fibrinolysis (clot breakdown)
 CLOTTING CASCADE

Normally the ingredients, called factors, act like a row of

dominoes toppling against each other to create a chain
reaction.
If one of the factors is missing this chain reaction cannot
proceed.
 VASCULAR PHASE
WHEN A BLOOD VESSEL IS DAMAGED,
VASOCONSTRICTION RESULTS.
THIS IS CAUSED BY TXA2 FROM ACTIVATED PLTS, AND
INJURED EPITHELIAL CELLS,
NERVOUS SYSTEM REFLEXES FROM PAIN,
DIRECT INJURY TO VASCULAR SMOOTH MUSCLE
 PLATELET PHASE
PLATELETS ADHERE TO THE DAMAGED SURFACE AND
FORM A TEMPORARY PLUG.
COAGULATION PHASE
THROUGH TWO SEPARATE PATHWAYS THE
CONVERSION OF FIBRINOGEN TO FIBRIN IS COMPLETE.
 THE CLOTTING MECHANISM

INTRINSIC EXTRINSIC
Collagen Tissue Thromboplastin
XII
XI VII
IX
VIII
X

V FIBRINOGEN
(I)
PROTHROMBIN THROMBIN
(II) (III) FIBRIN
FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE ACTIVATED TO
ALLOW CLOT DISINTEGRATION AND REPAIR OF THE
DAMAGED VESSEL.
 HEMOSTASIS

DEPENDENT UPON:
-Vessel Wall Integrity
-Adequate Numbers of Platelets
-Proper Functioning Platelets
-Adequate Levels of Clotting Factors
-Proper Function of Fibrinolytic Pathway
LABORATORY EVALUATION

-BLEEDING TIME (BT)

-PROTHROMBIN TIME (PT)
-PARTIAL THROMBOPLASTIN TIME (PTT)
-PLATELET COUNT
-THROMBIN TIME (TT)
 PLATELET COUNT
 NORMAL 100,000 - 400,000 CELLS/MM3

< 100,000 Thrombocytopenia

50,000 - 100,000 Mild Thrombocytopenia

< 50,000 Severe Thrombocytopenia

 BLEEDING TIME

- PROVIDES ASSESSMENT OF PLATELET COUNT AND

FUNCTION

NORMAL VALUE
2-8 MINUTES
 PROTHROMBIN TIME
-Measures Effectiveness of the Extrinsic Pathway

NORMAL VALUE
10-15 SECS
 PARTIAL THROMBOPLASTIN
TIME(PTT)/aPTT
-Measures Effectiveness of the Intrinsic
Pathway
-the coagulation factors measured: 1,2,5,7,10,11,12
- Also used to monitor the tx effect of heparin

NORMAL VALUE
25-40 SECS
 THROMBIN TIME
- Time for Thrombin To Convert Fibrinogen to Fibrin
-measures the time it takes for a clot to form in the plasma of a blood sample
containing an anticoagulant after an excessof thrombin has been added

-used to assess blood coagulation disorders

-the test is repeated with pooled plasma from normal pts

- A Measure of Fibrinolytic Pathway

NORMAL VALUE
9-13 SECS
 So What Causes Bleeding Disorders?

?
-VESSEL DEFECTS
-PLATELET DISORDERS
-FACTOR DEFICIENCIES
-OTHER DISORDERS

?
 VESSEL DEFECTS
-VITAMIN C DEFICIENCY

-BACTERIAL & VIRAL INFECTIONS

- ACQUIRED &
-HEREDITARY CONDITIONS
 Vascular defect - cont.
 Infectious and hypersensitivity vasculitides
- Rickettsial and meningococcal infections
- Henoch-Schonlein purpura (immune)
PLATELET DISORDERS
1. Thrombocytopenia
2. thrombocytopathy
THROMBOCYTOPENIA

INADEQUATE NUMBER
OF PLATELETS
THROMBOCYTOPATHY
• ADEQUATE NUMBER BUT ABNORMAL FUNCTION
 THROMBOCYTOPENIA

-DRUG INDUCED
-BONE MARROW FAILURE
-HYPERSPLENISM
-OTHER CAUSES
-OTHER CAUSES
 Lymphoma
 HIV Virus
 Idiopathic Thrombocytopenia Purpura (ITP)
 THROMBOCYTOPATHY

- UREMIA
- INHERITED DISORDERS
- MYELOPROLIFERATIVE DISORDERS
- DRUG INDUCED
 FACTOR DEFICIENCIES
(CONGENITAL)

-HEMOPHILIA A

-HEMOPHILIA B

-Von WILLEBRAND’S DISEASE

 FACTOR DEFICIENCIES

-HEMOPHILIA A (Classic Hemophilia)

• 80-85% of all Hemophiliacs
• Deficiency of Factor VIII
• Lab Results - Prolonged PTT

-HEMOPHILIA B (Christmas Disease)

10-15% of all Hemophiliacs
Deficiency of Factor IX
Lab Test - Prolonged PTT
 FACTOR DEFICIENCIES
-VON WILLEBRAND’S DISEASE
 Deficiency of VWF & amount of Factor VIII
 Lab Results - Prolonged BT, PTT
 OTHER DISORDERS
(ACQUIRED)
- ANTICOAGULANTS
 COUMARIN
 HEPARIN
- LIVER DISEASE
- MALABSORPTION
- BROAD-SPECTRUM ANTIBIOTICS
 INHIBITORS

Upto 30% of people with severe haemophilia A develop an

antibody to the clotting factor they are receiving for treatment.
These antibodies are known as inhibitors.

These patients are treated with high does of FVIIa for bleeds or
surgery. This overrides defect in FVIII or FIX deficiency.

Long term management involves attempting to eradicate

inhibitors by administering high dose FVIII (or FIX) in a
process called immune tolerance
Bleeding Disorders
Clinical Features of Bleeding
Disorders
Platelet Coagulation
disorders factor disorders
Site of bleeding Skin Deep in soft tissues
Mucous membranes (joints, muscles)
(epistaxis, gum,
vaginal, GI tract)
Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large, deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2 days),
usually mild often severe
Platelet Coagulation

Petechiae, Purpura Hematoma, Joint bl.

Petechiae
(typical of platelet disorders)

Do not blanch with

pressure
(cf. angiomas)
Not palpable
(cf. vasculitis)
Hemarthrosis
Hematoma
Petechiae
Purpura
Ecchymosis
Senile Purpura
Petechiae in patient
with Rocky Mountain
Spotted Fever
Henoch-Schonlein purpura

•
Ecchymoses
(typical of coagulation
factor disorders)
Coagulation factor disorders
• Inherited bleeding • Acquired bleeding
disorders disorders
• Hemophilia A and B • Liver disease
• Von Willebrands disease • Vitamin K
• Other factor deficiencies deficiency/warfarin
overdose
• DIC
 Hemophilia A and B
Hemophilia A Hemophilia
B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linked

recessive recessive

Incidence 1/10,000 males

1/50,000 males

Severity Related to factor level

<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild
injury
5-25% - Mild - bleeding with surgery
Hemophilia
Clinical manifestations (hemophilia A & B are
indistinguishable)
Hemarthrosis (most common)
Fixed joints

Soft tissue hematomas (e.g., muscle)

Muscle atrophy
Shortened tendons

Other sites of bleeding

Urinary tract
CNS, neck (may be life-threatening)

Prolonged bleeding after surgery or dental extractions

Hemarthrosis (acute)
Treatment Hemophilia A
• Mx of hemostasis
• Mx of bleeding episodes
• Tx and rehabilitation of pts with hemophilia synovitis
• Tx of pts with factor inhibitors
• Use of factor replacement products and adjuvant medications
Treatment of hemophilia A cont.

• Intermediate purity plasma products

• Virucidally treated
• May contain von Willebrand factor

• High purity (monoclonal) plasma products

• Virucidally treated
• No functional von Willebrand factor

• Recombinant factor VIII

• Virus free/No apparent risk
• No functional von Willebrand factor
Complications of therapy
• Formation of inhibitors (antibodies)
• 10-15% of severe hemophilia A patients
• 1-2% of severe hemophilia B patients

• Viral infections
• Hepatitis B Human parvovirus
• Hepatitis C Hepatitis A
• HIV Other
Treatment of hemophilia B
• Agent
• High purity factor IX
• Recombinant human factor IX

• Dose
• Initial dose: 100U/kg
• Subsequent: 50U/kg every 24 hours
von Willebrand Disease: Clinical Features

• von Willebrand factor

• Synthesis in endothelium and megakaryocytes

• Forms large multimer

• Carrier of factor VIII
• Anchors platelets to subendothelium
• Bridge between platelets
• Inheritance - autosomal dominant
• Incidence - 1/10,000
• Clinical features - mucocutaneous bleeding
 Treatment of von Willebrand Disease
• Cryoprecipitate
• Source of fibrinogen, factor VIII and VWF
• Only plasma fraction that consistently contains VWF
multimers

• DDAVP (deamino-8-arginine vasopressin)

•  plasma VWF levels by stimulating secretion from
endothelium
• Duration of response is variable
• Not generally used in type 2 disease
• Dosage 0.3 µg/kg q 12 hr IV

• Factor VIII concentrate (Intermediate purity)

• Virally inactivated product
 Vitamin K deficiency
• Source of vitamin K Green vegetables eg Sukuma wiki,
spinach parsley,Synthesized by
intestinal flora

• Required for synthesis Factors II, VII, IX ,X

Protein C and S

• Causes of deficiency Malnutrition

Biliary obstruction
Malabsorption
Antibiotic therapy

• Treatment :Vitamin K, Fresh frozen plasma

DIC

• Defined as a clinic-pathological syndrome characterized by

widespread intravascular fibrin formation in response to
excessive blood protease activity that overcomes the natural
anticoagulant mechanisms.

• There is acute /chronic types

 Common clinical conditions
associated with
Disseminated Intravascular
Coagulation
ctivation of both coagulation and fibrinolysis
Triggered by
• Sepsis • Obstetrical
complications
• Trauma • Amniotic fluid embolism
• Head injury • Abruptio placentae
• Fat embolism
• Vascular disorders
• Malignancy • Reaction to toxin (e.g.
snake venom, drugs)

• Immunologic disorders
• Severe allergic reaction
• Transplant rejection
Disseminated Intravascular
Coagulation (DIC)
Mechanism
Systemic activation
of coagulation

Intravascular Depletion of platelets

deposition of fibrin and coagulation factors

Thrombosis of small Bleeding

and midsize vessels
with organ failure
Pathogenesis of DIC

Release of
thromboplastic
material into Consumption of
circulation coagulation factors;
presence of FDPs
Coagulation Fibrinolysis
 aPTT
 PT
Fibrinogen  TT
Thrombin Plasmin
 Fibrinogen

Presence of plasmin
Fibrin  FDP
Monomers Fibrin(ogen)
Degradation Intravascular clot
Products  Platelets
Fibrin Schistocytes
Clot Elevated thrombomodulin
Plasmin
(intravascular)
Low prot C and
Disseminated Intravascular
Coagulation
Treatment approaches
• Treatment of underlying disorder

• Anticoagulation with [Link]-daparanoid

sodium, recombinant hirudin,recombinant tissue
factor pathway inhibitor

• Platelet transfusion

• Fresh frozen plasma

• Coagulation inhibitor concentrate (ATIII)

Classification of platelet
disorders
• Quantitative disorders
• Qualitative disorders
• Abnormal distribution
• Dilution effect • Inherited disorders (rare)
• Decreased production • Acquired disorders
• Increased destruction • Medications
• Chronic renal failure
• Cardiopulmonary bypass
 Thrombocytopenia

Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia
Liver Disease and Hemostasis

1. Decreased synthesis of II, VII, IX, X, XI, and

fibrinogen
2. Dietary Vitamin K deficiency (Inadequate intake or
malabsortion)
3. Dysfibrinogenemia
4. Enhanced fibrinolysis (Decreased alpha-2-
antiplasmin)
5. DIC
6. Thrombocytoepnia due to hypersplenism
Management of Hemostatic
Defects in Liver Disease
Treatment for prolonged PT/PTT
 Vitamin K 10 mg SQ x 3 days - usually ineffective
 Fresh-frozen plasma infusion
 25-30% of plasma volume (1200-1500 ml)
 immediate but temporary effect
Treatment for low fibrinogen
 Cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (Elevated D-dimer, low factor VIII,

thrombocytopenia
 Replacement therapy
 Vitamin K deficiency due to warfarin
overdose
Managing high INR values
Clinical situation Guidelines

INR therapeutic-5 Lower or omit next dose;

Resume therapy when INR is therapeutic

INR 5-9; no bleeding Lower or omit next dose;

Resume therapy when INR is therapeutic
Omit dose and give vitamin K (1-2.5 mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)

INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessary
Resume therapy at lower dose when INR therapeutic

Chest 2001:119;22-38s (supplement)

 Vitamin K deficiency due to warfarin
overdose
Managing high INR values in bleeding patients
inical situation Guidelines

NR > 20; serious bleedingOmit warfarin

Vitamin K 10 mg slow IV infusion
FFP or PCC (depending on urgency)
Repeat vitamin K injections every 12 hrs as neede

ny life-threatening bleeding Omit warfarin

Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs as neede

Chest 2001:119;22-38s (supplement)

Approach to Post-operative bleeding
1. Is the bleeding local or due to a hemostatic
failure?

1. Local: Single site of bleeding usually rapid with

minimal coagulation test abnormalities
2. Hemostatic failure: Multiple site or unusual
pattern with abnormal coagulation tests
2. Evaluate for causes of peri-operative
hemostatic failure

1. Preexisting abnormality
2. Special cases (e.g. Cardiopulmonary bypass)
3. Diagnosis of hemostatic failure

1. Review pre-operative testing

2. Obtain updated testing
 Laboratory Evaluation of
Bleeding
Overview
CBC and smear Platelet count Thrombocytopenia
RBC and platelet morphology TTP, DIC, etc.

Coagulation Prothrombin time Extrinsic/common pathways

Partial thromboplastin time Intrinsic/common
pathways
Coagulation factor assays Specific factor deficiencies
50:50 mix Inhibitors (e.g., antibodies)
Fibrinogen assay Decreased fibrinogen
Thrombin time Qualitative/quantitative
fibrinogen defects
FDPs or D-dimer Fibrinolysis (DIC)

Platelet function von Willebrand factor vWD

Bleeding time In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet
disorders and vWD
Platelet function tests Qualitative platelet disorders
 Laboratory Evaluation of the
Coagulation Pathways
Partial thromboplastin time Prothrombin time
(PTT) (PT)
Surface activating agent Thromboplastin
(Ellagic acid, kaolin) Tissue factor
Phospholipid Phospholipid
Calcium Calcium

Intrinsic pathway Extrinsic pathway

Thrombin time Common pathway

Thrombin

Fibrin clot
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
Thrombin Time

• Bypasses factors II-XII

• Measures rate of fibrinogen conversion to

fibrin

• Procedure:
• Add thrombin with patient plasma
• Measure time to clot

• Variables:
• Source and quantity of thrombin
Causes of prolonged Thrombin
Time
• Heparin
• Hypofibrinogenemia
• Dysfibrinogenemia
• Elevated FDPs or
paraprotein
• Thrombin inhibitors (Hirudin)
• Thrombin antibodies
Bleeding time and bleeding
• 5-10% of patients have a prolonged
bleeding time

• Most of the prolonged bleeding times are

due to aspirin or drug ingestion

• Prolonged bleeding time does not predict

excess surgical blood loss

• Not recommended for routine testing in

preoperative patients
Drugs and blood products used
for bleeding
Treatment Approaches to
the Bleeding Patient
• Red blood cells
• Platelet transfusions
• Fresh frozen plasma
• Cryoprecipitate
• Amicar
• DDAVP
• Recombinant Human factor VIIa
RBC transfusion therapy
Indications
• Improve oxygen carrying capacity of blood

• Bleeding

• Chronic anemia that is symptomatic

• Peri-operative management
 Red blood cell transfusions
Special preparation
CMV-negative CMV-negative patients Prevent CMV
transmission

Irradiated RBCs Immune deficient recipient Prevent

GVHD
or direct donor

Leukopoor Previous non-hemolytic Prevents reaction

transfusion reaction
CMV negative patients Prevents
transmission

Washed RBC PNH patients Prevents hemolysis

IgA deficient recipient Prevents
 Red blood cell transfusions
Adverse reactions
Immunologic reactions

Hemolysis RBC incompatibility

Anaphylaxis Usually unknown; rarely against
IgA
Febrile reaction Antibody to neutrophils
Urticaria Antibody to donor plasma proteins
Non-cardiogenic Donor antibody to leukocytes
pulmonary edema
 Red blood cell transfusions
Adverse reactions

Non-immunologic reactions

Congestive heart failure Volume

overload

Fever and shock Bacterial

contamination

Hypocalcemia Massive
transfusion
Platelet transfusions
• Source
• Platelet concentrate (Random donor)
• Pheresis platelets (Single donor)

• Target level
• Bone marrow suppressed patient (>10-20,000/µl)
• Bleeding/surgical patient (>50,000/µl)
Platelet transfusions -
complications
• Transfusion reactions
• Higher incidence than in RBC transfusions
• Related to length of storage/leukocytes/RBC
mismatch
• Bacterial contamination

• Platelet transfusion refractoriness

• Alloimmune destruction of platelets (HLA antigens)
• Non-immune refractoriness
• Microangiopathic hemolytic anemia
• Coagulopathy
• Splenic sequestration
• Fever and infection
• Medications (Amphotericin, vancomycin, ATG, Interferons)
 Fresh frozen plasma
• Content - plasma (decreased factor V and VIII)
• Indications
• Multiple coagulation deficiencies (liver disease, trauma)
• DIC
• Warfarin reversal
• Coagulation deficiency (factor XI or VII)
• Dose (225 ml/unit)
• 10-15 ml/kg
• Note
• Viral screened product
• ABO compatible
Cryoprecipitate
• Prepared from FFP
• Content
• Factor VIII, von Willebrand factor, fibrinogen
• Indications
• Fibrinogen deficiency
• Uremia
• von Willebrand disease
• Dose (1 unit = 1 bag)
• 1-2 units/10 kg body weight
 Hemostatic drugs
Aminocaproic acid (Amicar)
• Mechanism
• Prevent activation plaminogen -> plasmin
• Dose
• 50mg/kg po or IV q 4 hr
• Uses
• Primary menorrhagia
• Oral bleeding
• Bleeding in patients with thrombocytopenia
• Blood loss during cardiac surgery
• Side effects
• GI toxicity
• Thrombi formation
 Hemostatic drugs
Desmopressin (DDAVP)
• Mechanism
• Increased release of VWF from endothelium
• Dose
• 0.3µg/kg IV q12 hrs
• 150mg intranasal q12hrs
• Uses
• Most patients with von Willebrand disease
• Mild hemophilia A
• Side effects
• Facial flushing and headache
• Water retention and hyponatremia
Recombinant human factor VIIa (rhVIIa;
Novoseven)
• Mechanism
• Direct activation of common pathway

• Use
• Factor VIII inhibitors
• Bleeding with other clotting disorders
• Warfarin overdose with bleeding
• CNS bleeding with or without warfarin

• Dose
• 90 µg/kg IV q 2 hr
• “Adjust as clinically indicated”
Approach to bleeding disorders
Summary
• Identify and correct any specific defect of
hemostasis
• Laboratory testing is almost always needed to establish the
cause of bleeding

• Screening tests (PT,PTT, platelet count) will often allow

placement into one of the broad categories

• Specialized testing is usually necessary to establish a specific

diagnosis
• Use non-transfusional drugs whenever possible

• RBC transfusions for surgical procedures or large

blood loss
THANKS!