This document discusses coagulation proteins and bleeding disorders. It describes the coagulation cascade and how coagulation factors work together to form clots and prevent bleeding. Deficiencies in specific coagulation factors can cause bleeding disorders like hemophilia A and B which are caused by factor VIII and IX deficiencies. Other bleeding disorders discussed include liver disease, vitamin K deficiency, and disseminated intravascular coagulation. Tests for coagulation disorders and treatment approaches are also summarized.

1. Coagulation ProteinsCoagulation Proteins
andand
Bleeding DisordersBleeding Disorders
Marcelo dos SantosMarcelo dos Santos
B.Med.Lab.ScB.Med.Lab.Sc..

2. The Coagulation SystemThe Coagulation System
Primary HemostasisPrimary Hemostasis
-occurs within seconds
-predominantly arterial
Platelet Plug Formation

3. The Coagulation SystemThe Coagulation System
Secondary HemostasisSecondary Hemostasis
-occurs within minutes
-predominantly venous
Fibrin Clot Formation

4. Coagulation ProteinsCoagulation Proteins
Structure and FunctionStructure and Function

5. Coagulation CascadeCoagulation Cascade
Clot formation:
Factors XIII, XII, XI, X, IX, VIII,
VII, V, Prothrombin (II),
Fibrinogen (I)

6. Coagulation CascadeCoagulation Cascade
Clot formation prevention:
Antithrombin
Proteins C and S
Tissue factor-pathway inhibitor
(TFPI)
Factors II, VII, IX and X, and Proteins CFactors II, VII, IX and X, and Proteins C
and S are Vitamin K dependentand S are Vitamin K dependent

7. Coagulation CascadeCoagulation Cascade
Clot lysisClot lysis ::
Plasminogen PlasminPlasminogen Plasmin
(tPA and uPA are activated by(tPA and uPA are activated by
thrombin; inhibited by plasmin-thrombin; inhibited by plasmin-
activator inhibitors)activator inhibitors)
tPA/uPA

8. Coagulation CascadeCoagulation Cascade
Basic principles of coagulation cascadeBasic principles of coagulation cascade::
 Inert factors constantly present in theInert factors constantly present in the
plasmaplasma
 Activated in a cascade-like fashionActivated in a cascade-like fashion
 Self-augmentation of the cascadeSelf-augmentation of the cascade
 Anti-thrombotic and fibrinolytic proteinsAnti-thrombotic and fibrinolytic proteins
and platelets are simultaneously activatedand platelets are simultaneously activated

9. Coagulation cascadeCoagulation cascade
Factor VII+Tissue Factor
Factor VIII
Prothrombin
Thrombin
Fibrinogen Fibrin
Factor V
Factor XII
Factor XI Factor XIa
Factor XIIIa
Clot
Plasminogen Plasmin
tPA / uPA
Factor IX
Factor IXa
Factor X
Factor Xa
Platelet
activation
Protein C / Protein S
Antithrombin
TFPI
VIIa

10. Coagulation TestsCoagulation Tests
Diagnostic tests:Diagnostic tests:
 Activated Partial Thromboplastin TimeActivated Partial Thromboplastin Time (aPTT)(aPTT)
 Prothrombin TimeProthrombin Time (PT)(PT) InternationalInternational
Normalized RatioNormalized Ratio (INR)(INR)
 Thrombin TimeThrombin Time
 Factor levelsFactor levels

11. Coagulation TestsCoagulation Tests
aPTTaPTT (citrated plasma +Ca + phospholipid +(citrated plasma +Ca + phospholipid +
kaolin) -kaolin) - 28-42 sec28-42 sec
PT (PT (citrated plasma +Ca+thromboplastin)citrated plasma +Ca+thromboplastin) ––
12-14 sec12-14 sec oror 60-100%60-100%
INRINR (calculated) -(calculated) - 1-1.31-1.3
Thrombin timeThrombin time (patient’s plasma + thrombin)-(patient’s plasma + thrombin)-
11-13 sec11-13 sec

12. Coagulation TestsCoagulation Tests
aPTT is affected by the activity of factorsaPTT is affected by the activity of factors XI, IX,XI, IX,
VIII -VIII - the intrinsic pathwaythe intrinsic pathway
PT is affected by the activity of factorPT is affected by the activity of factor VII -VII - thethe
extrinsic pathwayextrinsic pathway
aPTTaPTT andand PT both affected by the activity of factorsPT both affected by the activity of factors
X, V, II (prothrombin) and I (fibrinogen) -X, V, II (prothrombin) and I (fibrinogen) - thethe
common pathwaycommon pathway

13. Coagulation TestsCoagulation Tests
Because of factor VII short half-life,Because of factor VII short half-life,
PT is prolongedPT is prolonged beforebefore PTT in allPTT in all
disorders affecting the commondisorders affecting the common
pathway (vitamin K deficiency, liverpathway (vitamin K deficiency, liver
failure)failure)

14. Bleeding DisordersBleeding Disorders

15. Bleeding DisordersBleeding Disorders
1.1. Coagulation factors deficiency:Coagulation factors deficiency:
- may be- may be inheritedinherited oror acquiredacquired
- can cause life-threatening bleeding- can cause life-threatening bleeding oror
be completely asymptomaticbe completely asymptomatic
- the bleeding is usually into- the bleeding is usually into deep tissuesdeep tissues
(muscles, joints, internal organs)(muscles, joints, internal organs)
- causes- causes prolongationprolongation ofof PT/aPTTPT/aPTT

16. Coagulation Factors DeficiencyCoagulation Factors Deficiency
 Inherited:Inherited:
- Factors VIII- Factors VIII//IXIX (hemophilia)(hemophilia)
- Factor XI- Factor XI
- Other factors- Other factors
 Acquired:Acquired:
- DIC- DIC
- Vitamin K deficiency- Vitamin K deficiency
- Liver failure- Liver failure

17. HemophiliaHemophilia
 Deficiency of factorsDeficiency of factors VIII or IXVIII or IX
 X-linked inheritanceX-linked inheritance –– female carriers,female carriers,
affected malesaffected males (30% - new mutations)(30% - new mutations)

18. HemophiliaHemophilia
 Deficiency of factorsDeficiency of factors VIII or IXVIII or IX
 X-linked inheritanceX-linked inheritance –– female carriers, affectedfemale carriers, affected
malesmales (30% - new mutations)(30% - new mutations)
 First mentioned in Talmud:First mentioned in Talmud: if a male childif a male child
bled profusely followingbled profusely following Brith Mila,Brith Mila, hishis
brothers were exempted from circumcisionbrothers were exempted from circumcision
 Among the descendants of Queen VictoriaAmong the descendants of Queen Victoria
were numerous carriers and affected maleswere numerous carriers and affected males

19. HemophiliaHemophilia

20. HemophiliaHemophilia
 IncidenceIncidence - 1:10,000 births (A)- 1:10,000 births (A)
1:30,000 (B)1:30,000 (B)
 Hemophilia in IsraelHemophilia in Israel - about 400 patients- about 400 patients
 Severe bleedingSevere bleeding : < 1% factor activity: < 1% factor activity
(spontaneous bleeding)(spontaneous bleeding)
Moderate bleedingModerate bleeding : 1-5% activity (mostly: 1-5% activity (mostly
traumatic bleeding)traumatic bleeding)
Mild bleedingMild bleeding : 5-20% activity (only traumatic: 5-20% activity (only traumatic
bleeding)bleeding)

21. Type of mutations in hemophiliaType of mutations in hemophilia
AA

22. Coagulation cascadeCoagulation cascade
Factor VIIa / Tissue Factor
Factor VIII
Prothrombin
Thrombin
Fibrinogen Fibrin
Factor V
Factor XII
Factor XI Factor XIa
Factor XIII
Clot
Plasminogen Plasmin
tPA / uPA
Factor IX
Factor IXa
Factor X
Factor Xa
Platelet
activation
Protein C / Protein S
Antithrombin
TFPI

23. HemophiliaHemophilia
 Therapy is byTherapy is by factor replacementfactor replacement::
- cryoprecipitate- cryoprecipitate
- purified factor recombinant factor VIII- purified factor recombinant factor VIII
- DDAVP (mild disease)- DDAVP (mild disease)
 Principles of therapy:Principles of therapy:
- prevention- prevention (pre-operative)(pre-operative)
- early therapy initiation- early therapy initiation (self-(self-
administration)administration)
- hemophilia centers (Israel-Tel-haShomer)- hemophilia centers (Israel-Tel-haShomer)

24. HemophiliaHemophilia
 Recurrent exposure to factor VIII in patients withRecurrent exposure to factor VIII in patients with
severe factor deficiency (<1%) may lead tosevere factor deficiency (<1%) may lead to
development ofdevelopment of anti-factor VIII antibodiesanti-factor VIII antibodies
 IncidenceIncidence : 15-30%, usually > 90 exposures: 15-30%, usually > 90 exposures
 Treatment of inhibitorTreatment of inhibitor :: high dose factor VIII,high dose factor VIII,
porcine factor VIII, recombinant factor VIIaporcine factor VIII, recombinant factor VIIa
 Anti-factor VIII antibodies can also develop inAnti-factor VIII antibodies can also develop in
non-hemophilic patientsnon-hemophilic patients (autoimmunity, post-(autoimmunity, post-
partum, cancer and different drugs)partum, cancer and different drugs)

25. Factor XI DeficiencyFactor XI Deficiency
 Autosomal recessiveAutosomal recessive
 A number of mutations withA number of mutations with different severitydifferent severity
of bleedingof bleeding
 In Ashkenazi Jews:In Ashkenazi Jews: 10% carriers10% carriers
1:400 affected1:400 affected
 Clinical manifestations when factor levels fallClinical manifestations when factor levels fall
below 15%below 15%
 PostPost trauma/surgerytrauma/surgery bleeding is commonbleeding is common

26. Factor XI DeficiencyFactor XI Deficiency
 Screening by aPTT isScreening by aPTT is mandatorymandatory forfor
Ashkenazi Jewish patients before surgeryAshkenazi Jewish patients before surgery
 Treatment by FFP is indicatedTreatment by FFP is indicated before surgerybefore surgery
and for 5-7 daysand for 5-7 days following operationfollowing operation
 Screening forScreening for inhibitorinhibitor (acquired anti-factor XI(acquired anti-factor XI
antibody) among treated patients (those withantibody) among treated patients (those with
very low factor levels who received FFP)very low factor levels who received FFP)

27. DICDIC
 Not aNot a diseasedisease, but a, but a syndromesyndrome associated with manyassociated with many
underlying conditionsunderlying conditions
 Initiated by anInitiated by an activation of the coagulation cascadeactivation of the coagulation cascade
due to a thrombogenic stimulus withdue to a thrombogenic stimulus with massivemassive
thrombin generation,thrombin generation, leading toleading to consumption ofconsumption of
clotting factorsclotting factors andand activation of fibrinolysisactivation of fibrinolysis
 May cause either bleeding or disseminated thrombosisMay cause either bleeding or disseminated thrombosis

29. DICDIC
Underlying diseases:Underlying diseases:
 Infectious diseases (mainly bacterial)Infectious diseases (mainly bacterial)
 Surgery and traumaSurgery and trauma
 BurnsBurns
 Obstetric complications (abruptio placenta,Obstetric complications (abruptio placenta,
amniotic fluid emboli)amniotic fluid emboli)
 Malignant diseases (chronic DIC)Malignant diseases (chronic DIC)
 Others (e.g. – ABO incompatible bloodOthers (e.g. – ABO incompatible blood
transfusion)transfusion)

30. DICDIC
Laboratory findings:Laboratory findings:
- thrombocytopenia- thrombocytopenia
- prolonged PT/aPTT- prolonged PT/aPTT
- elevated fibrinolytic markers- elevated fibrinolytic markers
(D-Dimer)(D-Dimer)
- low fibrinogen- low fibrinogen
- microangiopathic changes- microangiopathic changes

31. DICDIC
Clinical findings:Clinical findings:
 Bleeding, thrombosisBleeding, thrombosis
 Renal dysfunctionRenal dysfunction
 Liver dysfunctionLiver dysfunction
 Respiratory dysfunctionRespiratory dysfunction
 CNS manifestationsCNS manifestations
 ShockShock
 Chronic DIC (mainly thrombosis)Chronic DIC (mainly thrombosis)

32. DICDIC
Therapy:Therapy:
 Vigorous treatment of underlying conditionVigorous treatment of underlying condition
 Replacement therapy in case of bleeding:Replacement therapy in case of bleeding:
- FFP- FFP
- Cryoprecipitate- Cryoprecipitate
- Platelets- Platelets
- Packed cells- Packed cells
 Heparin in case of thrombosisHeparin in case of thrombosis

33. Liver FailureLiver Failure
 Most of the coagulation factors are producedMost of the coagulation factors are produced
by the liverby the liver
 Liver failure causes factor deficiency withLiver failure causes factor deficiency with
prolongation ofprolongation of PTPT followed by prolongationfollowed by prolongation
of aPTTof aPTT
 Prolonged PT is a sign ofProlonged PT is a sign of terminal liverterminal liver
failurefailure in patients with acute and chronic liverin patients with acute and chronic liver
diseasedisease
 Therapy:Therapy: FFPFFP, liver transplantation, liver transplantation

34. Vitamin K DeficiencyVitamin K Deficiency
 Vitamin KVitamin K is needed for synthesis of factorsis needed for synthesis of factors
II, VII, IX and X, and proteins C and SII, VII, IX and X, and proteins C and S
 Vitamin source - greenVitamin source - green ““leafyleafy”” vegetablesvegetables
(spinach, broccoli, avocado)(spinach, broccoli, avocado)
 Deficiency is caused byDeficiency is caused by low dietary intakelow dietary intake
coupled withcoupled with antibiotic therapy or cholestasisantibiotic therapy or cholestasis
(e.g.(e.g. –– hospitalized patients)hospitalized patients)
 PT is affectedPT is affected beforebefore aPTTaPTT
 Therapy: FFP, vitamin KTherapy: FFP, vitamin K