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BLEEDING & CLOTTING DISORDERS
Dr. M. A SofiMD; FRCP (London);
FRCPEdin; FRCCSEdin
BLEEDING DISORDERS
HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE
Hemostasis
BV Injury
PlateletAggregation
PlateletActivation
Blood Vessel Constriction
Coagulation Cascade
Stable Hemostatic Plug
Fibrin formation
Reduced
Blood flow
Tissue Factor
Primary hemostatic plug
Neural
Lab Tests•CBC-Plt•BT,(CT)•PT•PTT
Plt StudyMorphologyFunctionAntibody
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)
VASCULAR PHASE
WHEN A BLOOD VESSEL IS DAMAGED,
VASOCONSTRICTION RESULTS.
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
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN(II) (III)
(I)V
X
Tissue ThromboplastinCollagen
VII
XII
XI
IXVIII
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
PLATELET COUNTBLEEDING TIME (BT)PROTHROMBIN TIME (PT)PARTIAL THROMBOPLASTIN
TIME (PTT)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 Measures Effectiveness of the
Intrinsic Pathway
Mnemonic - PITT
NORMAL VALUE 25-40 SECS
THROMBIN TIME
Time for Thrombin To Convert Fibrinogen Fibrin
A Measure of Fibrinolytic Pathway
NORMAL VALUE 9-13 SECS
What Causes Bleeding Disorders?
VESSEL DEFECTSPLATELET DISORDERSFACTOR DEFICIENCIESOTHER 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
THROMBOCYTOPENIA
THROMBOCYTOPATHY
INADEQUATE NUMBER OF PLATELETS
THROMBOCYTOPENIA
THROMBOCYTOPENIA
DRUG INDUCED BONE MARROW FAILUREHYPERSPLENISMOTHER CAUSES
OTHER CAUSES
LymphomaHIV VirusIdiopathic Thrombocytopenia Purpura (ITP)
THROMBOCYTOPATHY UREMIA INHERITED DISORDERS MYELOPROLIFERATIVE
DISORDERS DRUG INDUCED
FACTOR DEFICIENCY (CONGENITAL)
HEMOPHILIA A
HEMOPHILIA B
von WILLEBRAND’S DISEASE
FACTOR DEFICIENCIESHEMOPHILIA A (Classic
Hemophilia)80-85% of all HemophiliacsDeficiency of Factor VIIILab Results - Prolonged PTT
HEMOPHILIA B (Christmas Disease)
10-15% of all HemophiliacsDeficiency of Factor IXLab Test - Prolonged PTT
FACTOR DEFICIENCIES
VON WILLEBRAND’S DISEASEDeficiency of VWF & amount of Factor VIII
Lab Results - Prolonged BT, PTT
OTHER DISORDERS (ACQUIRED)
ORAL ANTICOAGULANTSCOUMARINHEPARIN
LIVER DISEASE MALABSORPTION BROAD-SPECTRUM
ANTIBIOTICS
INHIBITORS
30% of people with haemophilia 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.
Longterm management involves attempting to eradicate inhibitors by administering high dose FVIII (or FIX) in a process called immune tolerance
Clinical Features of Bleeding Disorders
Platelet factor Coagulation disorders 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 rareCommon
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate,
Delayed (1-2 days), usually mild often severe
Coagulation factor disorders
• Inherited bleeding disorders– Hemophilia A and B– vonWillebrands disease– Other factor deficiencies
• Acquired bleeding disorders– Liver disease– Vitamin K deficiency/warfarin overdose– DIC
Hemophilia A Hemophilia BCoagulation factor deficiency
Factor VIII Factor IX
Inheritance X-linked recessive X-linked recessive
Incidence 1/10,000 males 1/50,000 males
Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma
Complications Soft tissue bleeding
Hemophilia A and B
• Disorder caused by deficiency of clotting factor VIII.
• Inherited but acquired forms do exist, largely in older patients, due to auto-antibodies directed against factor VIII or hematological malignancy.
• Severity of disease depends upon levels of remaining factor activity, with normal range expressed as 50-200%
HEMOPHELIA
Severity of factor VIII deficiency
SeverityFactor VIII
activity levelAge of
presentationPercentage of sufferers
Severe disease
<1% Infancy 43-70%
Moderate disease
1-5%Before 2 years 15-26%
Mild disease >5%Older than 2 years 15-31%
HemophiliaClinical manifestations (hemophilia A & B are
indistinguishable)
Hemarthrosis (most common)Fixed joints
Soft tissue hematomas (e.g., muscle)Muscle atrophyShortened tendons
Other sites of bleedingUrinary tractCNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions
Hemarthrosis (acute)
Signs and symptoms• Depending on the level
of FVIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage.
• Signs of hemorrhage include:
• General: Weakness, orthostasis, tachycardia, tachypnea
• Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
• CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
• Gastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal pain
• Genitourinary: Hematuria, renal colic, and post circumcision bleeding
PRESENTATION
Laboratory studies for suspected hemophilia include:
• Complete blood cell count
• Coagulation studies• FVIII assayExpected laboratory values are:
• Hemoglobin/hematocrit: Normal or low
• Platelet count: Normal• Bleeding time: Norrmal• Prothrombin time:
Normal
• Activated partial thromboplastin time (aPTT):
• Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophilia
Screening tests include:• PT • aPTT (Normal aPTT does not
exclude the possibility of mild hemophilia)
• Platelet count
Laboratory findings:
Treatment of hemophilia A• 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
Dosing guidelines for hemophilia A
• Mild bleeding– Target: 30% dosing q8-12h; 1-2 days (15U/kg)– Hemarthrosis, oropharyngeal or dental, epistaxis,
hematuria• Major bleeding
– Target: 80-100% q8-12h; 7-14 days (50U/kg)– CNS trauma, hemorrhage, lumbar puncture– Surgery– Retroperitoneal hemorrhage– GI bleeding
• Adjunctive therapy– -aminocaproic acid (Amicar) or DDAVP (for mild
disease only)
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–HIVOther
Treatment of hemophilia B
• Agent –High purity factor IX–Recombinant human factor IX
• Dose–Initial dose: 100U/kg–Subsequent: 50U/kg every 24 hours
This is the most common hereditary coagulopathy in humans. It can be congenital or acquired. Pathophysiology
• Von Willebrand's disease (vWD) results from the deficiency or abnormal function of von Willebrand factor (vWF).
• vWF is a multimeric glycoprotein encoded for by gene map locus 12p13.
• It is made in the endothelium and stored in Weibel-Palade bodies. It has two main functions:
• It assists in platelet plug formation by attracting circulating platelets to the site of damage.
• It binds to coagulation factor VIII preventing its clearance from the plasma.
Von Willebrand's Disease
Von Willebrand factorVon Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome
Epidemiology• Prevalence is as high as 1-2% in the
general population on unselected screening.
• Worldwide incidence is around 125 per million with between 0.5 and 5 per million being severely affected.
• Most patients have mild disease.• It is more common in females.• It is more severe with blood type O.
Von Willebrand's Disease
EtiologyI. Hereditary - three types
• vWD Type I, vWD Type II, and vWD Type III• Within the three inherited types of vWD there are
various subtypes. II. Acquired - also called pseudo-von Willebrand's
disease or platelet-type; it is frequently found in:• Lymphoproliferative• Myeloproliferative disorders• Solid tumors• Immunological disorders• Cardiovascular disorders e.g., aortic stenosis, • Wilms'tumor, • Hypothyroidism.
Von Willebrand's Disease
Laboratory evaluation of von Willebrand disease
• Classification– Type 1 Partial quantitative
deficiency– Type 2 Qualitative deficiency– Type 3 Total quantitative deficiency
• Diagnostic tests: vonWillebrand typeAssay 1 2 3
vWF antigen ß Normal ßßvWF activity ß ß ßßMultimer analysis Normal Normal
Absent
Types of hereditary von Willebrand's disease (vWD)Type 1 60-80% Quantitative
defect (19-45% of enzyme level present)
• Heterozygous for defective gene
• Inherited as AD
• Normal lifespan• Occasionally easy
bruising and/or menorrhagia
• Bleeding after dental work, major surgery
Type 2 20-30% Qualitative defect - multimers abnormal or subgroups absent
Usually AD inheritance (rarely AR)
Bleeding tendency variesFour subtypes:2A, 2B, 2M, 2N
Type 3 Rare - the most severe form; 1-5% of cases
Quantitative - levels very low or undetectable
• Homozygous for defective gene
• AR inheritance
• No vWF antigen
• Low factor V
• Severe mucosal bleeding
• May have haemarthrosis (as in haemophilia
Platelet type
Rare - fewer than 70 cases described
Functional mutations of vWF receptor on platelet
• Autosomal dominant
Von Willebrand's Disease
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
Synthesized by intestinal flora
• Required for synthesis Factors II, VII, IX ,XProtein C and S
• Causes of deficiency MalnutritionBiliary obstruction
MalabsorptionAntibiotic therapy
• Treatment Vitamin KFresh frozen plasma
Common clinical conditions associated withDisseminated Intravascular Coagulation
• Sepsis
• Trauma
– Head injury– Fat embolism
• Malignancy
• Obstetrical complications– Amniotic fluid embolism– Abruptio placentae
• Vascular disorders
• Reaction to toxin (e.g. snake venom, drugs)
• Immunologic disorders– Severe allergic reaction– Transplant rejection
Activation of both coagulation and fibrinolysis
Triggered by
Disseminated Intravascular Coagulation (DIC)Mechanism
Systemic activationof coagulation
Intravasculardeposition of fibrin
Depletion of plateletsand coagulation factors
BleedingThrombosis of smalland midsize vessels
with organ failure
Pathogenesis of DIC
Coagulation Fibrinolysis
Fibrinogen
FibrinMonomers
FibrinClot
(intravascular)
Fibrin(ogen)Degradation
Products
Plasmin
Thrombin Plasmin
Release of thromboplastic material into
circulation
Consumption ofcoagulation factors;presence of FDPs
aPTT PT TT
Fibrinogen
Presence of plasmin FDP
Intravascular clot Platelets
Schistocytes
Disseminated Intravascular CoagulationTreatment approaches
• Treatment of underlying disorder
• Anticoagulation with heparin
• Platelet transfusion
• Fresh frozen plasma
• Coagulation inhibitor concentrate (ATIII)
Classification of platelet disorders
• Quantitative disorders
– Abnormal distribution
– Dilution effect– Decreased
production– Increased
destruction
• Qualitative disorders
– Inherited disorders (rare)
– Acquired disorders• Medications• Chronic renal
failure• Cardiopulmonar
y bypass
Thrombocytopenia
Immune-mediatedIdioapthicDrug-inducedCollagen vascular diseaseLymphoproliferative diseaseSarcoidosis
Non-immune mediatedDICMicroangiopathic 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
Treatment Approaches tothe Bleeding Patient
• Red blood cells• Platelet transfusions• Fresh frozen plasma• Cryoprecipitate• Aminocaproic acid• DDAVP• Recombinant Human factor VIIa
RBC transfusion therapyIndications
• Improve oxygen carrying capacity of blood–Bleeding–Chronic anemia that is symptomatic
–Peri-operative management
Red blood cell transfusionsAdverse reactions
Non-immunologic reactions
Congestive heart failure Volume overload
Fever and shock Bacterial contamination
Hypocalcemia Massive transfusion
Transfusion-transmitted disease
Infectious agent Risk
HIV ~1/500,000Hepatitis C 1/600,000Hepatitis B 1/500,000Hepatitis A <1/1,000,000HTLV I/II 1/640,000CMV 50% donors are sero-positiveBacteria 1/250 in platelet transfusionsCreutzfeld-Jakob disease UnknownOthers Unknown
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 drugsAminocaproic 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 drugsDesmopressin (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;
• 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 disordersSummary
• 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
THANK YOUFOR
ATTENTION