BLEEDING & CLOTTING DISORDERS Dr. M. A Sofi MD; FRCP (London); FRCPEdin; FRCCSEdin

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