Disorder of Coagulation

Maria Verena R. Remudaro, MD, FPCP, FPSMO

Coagulation Pathway
Hemophilia A & B
´ x-linked deficiencies of coagulation factors
´ 1 in 10,000 males worldwide
´ Hemophilia A or classic hemophilia (80%)
´ mutation in F8 gene
´ Inversion of the intron 22 sequence (40% of hemophilia A)
´ Hemophilia B – mutation in F9 gene
´ Exhibit life-long recurrent bleeding episodes into joints,
muscles, & closed spaces, either spontaneously or following
injury
 Hemophilia
mild Moderate Severe
Residual activity of 6-30% 1-5% <1%
FVIII or FIX
Clinical Bleeding due to Hemarthrosis (knees, elbows, ankles,
manifestation trauma shoulders, hip) spontaneously ! chronic
hemarthroses (debilitating)
bleeding after major Bleeding into soft tissues, & muscles (may
trauma or during lead to compartment syndrome) after minor
pre-surgery lab trauma or spontaneously
tests (>25% Bleeding into the oropharyngeal paces,
residual activity) CNS & retroperitoneum (pseudotumor
syndrome) is life-threatening
Hematuria
Laboratory tests Prolonged aPTT, normal bleeding time, normal platelet count,
determine FVIII or FIX clotting activity
Hemophilia
´ Without treatment – limited life expectancy
´ Cryoprecipitate
´ enriched with FVIII protein (each bag contains 80 IU)
´ Commonly used treatment decades ago
´ Still used in some developing countries
´ Increased risk of bloodborne diseases
´ Factor replacement therapy (FVIII or FIX)
´ For bleeding episode or prophylactic treatment
Hemophilia
´ Primary prophylaxis
´ strategy for maintaining the missing clotting factor at levels >1% on a
regular basis to prevent bleeds
´ 3 days/week for Hemophilia A
´ 2 days/week for Hemophilia B

´ Limiting factors of prophylaxis:

´ High cost
´ Difficulties in accessing peripheral veins in young patients
´ Potential infections
´ Potential thrombotic risks for long-term central vein catheters
Hemophilia

´ General considerations of treatment of bleeds

´ Treatment should begin as soon as possible
´ Symptoms often precede objective evidence of bleeding
´ Superior efficacy of early therapeutic intervention ! Classic symptoms
of bleeding into the joint, headaches or automobile accidents require
prompt replacement & further laboratory investigation
´ Drugs that hamper platelet function should be avoided; to control
pain, ibuprofen or propoxyphene are preferred
Hemophilia
´ 1 unit = amount of FVIII (100 ng/ml) or FIX (5 ug/ml) in 1 ml of
normal plasma
´ Formula to raise circulating levels to 100%

´ FVIII dose (IU) = (target FVIII-FVIII baseline levels) x BW (kg)

x 0.5U/kg
´ FVIII half life is 8-12 hrs – injections 2x a day
´ FIX dose (IU) = (target FVIII-FVIII baseline levels) x BW (kg) x
1U/kg
´ FIX half life is 24hrs – once a day injections
Hemophilia

Condition Factor levels requirement

Mild bleeds (uncomplicated hemarthroses
or superficial hematomas)
Severe hemarthroses
Large hematomas
Serious bleeding (oropharyngeal spaces,
CNS, retroperitoneum)
Prophylactic replacement for surgery
Oral surgery
Level of 30-50%
Initial therapy – 30-50%
Additional doses – maintain levels of 15-
20% for 2-3 days
level of <50% for 1 wk
Sustained levels of 50-100% for 7-10
days
100% for 7-10 days
100% for 1-3 days + antifibrinolytics
Hemophilia
´ DDAVP (desmopressin)
´ Synthetic vasopressin analogue
´ Causes transient rise in FVIII & VWF by release from endothelial
cells
´ Determine response in mild to moderate hemophilia
´ No response in severe hemophilia
´ More than 3 consecutive doses become ineffective ! give FVIII
replacement
´ Ε-aminocaproic acid or tranexamic acid
´ Antifibrinolytic
´ Used in bleeding in gums, GIT & during oral surgery
´ Not indicated to control hematuria
 Hemophilia
´ Inhibitor formation to FVIII & FIX– major complication of hemophilia
treatment
´ Suspected when patients do not respond to factor replacement at
therapeutic doses
´ To confirm presence of inhibitor is aPTT with normal plasma –
abnormally prolonged in inhibitor patients
´ Therapy has 2 goals:
´ Control acute bleeding episodes
´ Human or porcine FVIII, prothrombin complex concentrates, or activated
PCCs or recombinant activated FVII
´ Eradication of inhibitor
´ Immune tolerance induction
´ + anti-CD20 monoclonal antibody
Hemophilia
´ Infectious diseases
´ HCV – major cause of morbidity & 2nd leading cause of death
(1970-1985)
´ HIV
´ Emerging clinical problems – increase in population of adults
beyond middle age
´ Severe arthropathy & chronic pain
´ HTN, obesity, physical inactivity
´ Cancer – common cause of mortality in aging hemophilia
patients
• HIV- & HCV-related malignancies
• HCC in HIV negative patients
Hemophilia

´ Management of carriers
´ Measure the factor level to recognize those at risk of bleeding
(<50%) & to optimize preoperative & postoperative management
´ During pregnancy – 2-3x increase of FVIII
´ After delivery – rapid fall of clotting factors
´ Prevent bleeding by infusion of FVIII to 50-70% for 3 days
(vaginal delivery) or 5 days (CS)
´ Mild cases – use DDAVP &/or antifibrinolytic drugs
 Factor XI deficiency

´ Activates FIX
´ 2 pathways for the
formation of XI
´ Rare bleeding disorder
´ Autosomal recessive
´ Prevalent among
Ashkenazi & Iraqi Jews
´ Mutations in FXI gene
Factor XI deficiency

´ Heterozygous patients with moderate deficiency – level

ranges from 20-70 U/dL (normal rage – 70-150 U/dL)
´ Homozygous or double heterozygote – level are 1-20 u/dL
´ Mucocutaneous hemorrhages are common (bruises, gum
bleeding, epistaxis, hematuria, menorrhagia)
Factor XI deficiency

´ Infusion of FFP
´ FXI replacement therapy q other day (half life of 40-70 h)
´ Antifibrinolytic drugs
´ Severe bleeding – use of PCC/aPCC or recombinant
activated FVII
Other rare congenital bleeding disorders
´ Deficiencies of FII, FV, FVII, FXI, FXIII, fibrinogen
´ Autosomal recessive
´ No pathognomonic clinical manifestation
´ Asymptomatic (dysfibrinogenemia or FVII deficiency) to life-
threatening (FX or FXIII deficiency)
´ Mucocutaneous bleeding is more common; hemarthroses are
rare
´ FVII – isolated abnormal PT
´ FII, FV, FX, fibrinogen – prolonged PT & aPTT
Other inherited coagulation disorders
 Familial multiple coagulation deficiencies
´ Combined deficiency of FV & FVIII
´ Mutation in the ER/Golgi intermediate compartment (ERGIC) gene -
53) or multiple coagulation factor deficiency 2 (MCFD2) gene
´ 5% residual clotting activity of each factor
´ Mild bleeding tendencies
´ Multiple deficiencies of Vitamin K-dependent clotting factors
´ Mutations in genes encoding the γ-carboxylase & vitamin K epoxide
reductase complex 1 ! defective enzymes ! reduced activity
´ Respond to Vitamin K
´ Replacement therapy with FFP or PCC – for severe bleeding
Disseminated intravascular
coagulation
´ Clinicopathologic syndrome
´ Widespread intravascular
fibrin formation in response
to excessive blood protease
activity that overcomes the
anticoagulant mechanism
´ Mortality – 30-80%
´ Depending on underlying
disease, severity of DIC,
age
DIC

Suppression of
physiologic
Sustained activation
anticoagulant
of coagulation
mechanisms & abnormal
fibrinolysis
DIC
´ Clinical manifestations are ´ Purpura fulminans – severe
related to imbalance of form of DIC resulting from
hemostasis thrombosis of extensive
areas of the skin
´ Bleeding from venipuncture
sites
´ Severe hemorrhage from
GIT, lungs, CNs
 DIC
´ No single test that establishes the diagnosis
´ aPTT, PT, TT– prolonged
´ markers of fibrin degradation products – elevated
´ Most sensitive test
´ Platelet – low (<10,000/uL) or rapid decline
´ Red cell count – hemolysis
´ Analysis of blood smear – schistocytes (fragmented RBC)
´ D-dimer - high
´ High grade DIC – levels of antithrombin III or plasminogen
activity <60% normal
Chronic DIC
´ Low grade, compensated DIC
´ Giant hemangioma, metastatic carcinoma, dead fetus
syndrome
´ FDP & D-dimer – elevated
´ aPTT, PT, fibrinogen – normal to high
´ Platelet – normal to mild thrombocytopenia
´ Red cell fragmentation
DIC

´ Differential diagnosis
´ Severe liver disease, portal hypertension
´ Thrombocytopenia, prolonged PT, red cell fragmentation
´ Laboratory parameters do not change rapidly
´ Microangiopathic disorders (thrombotic thrombocytopenic
purpura)
´ Thrombocytopenia, red cell fragmentation, multiorgan failure
´ No consumption f clotting factors or hyperfibrinolysis
DIC
´ Treat underlying cause
´ Transfusion scheme is adjusted according to patient’s clinical &
laboratory evolution
´ FFP and/or platelet concentrate – with active bleeding or high risk of
bleeding (invasive procedures, after chemotherapy)
´ Cryoprecipitate - Low levels of fibrinogen
´ PT (>1.5 times the normal – good indicator of severity of clotting
factor consumption
´ low dose continuous heparin – low grade DIC
´ Antifibrinolytic drugs to reduce bleeding but given with heparin
´ Protein C concentrate – purpura fulminans associated with acquired
protein C deficiency & meningococcemia
Vitamin K deficiency
´ Causes
´ Inherited deficiency of the functional activity of the enzymes
´ Amount of Vitamin K in the diet
´ The use of broad spectrum antibiotic
´ Disease or surgical interventions that affect the absorption of
vitamin K
´ Chronic liver diseases
´ Neonatal vitamin K deficiency
Vitamin K deficiency
´ Management
´ Vitamin K
´ FPP – for ongoing bleeding or need for immediate correction
before surgical intervention
´ PCC – but avoided in liver diseases due to risk of thrombosis
´ For those taking warfarin, warfarin is given at a low dose
´ Recombinant FVIIa – low doses for a limited number of
injections for those given with anticoagulant for emergency
surgical intervention
Coagulation disorders associated with liver
failure
´ Liver – site of synthesis & clearance of most procoagulant,
natural anticoagulant proteins and components of the
fibrinolytic system
´ Liver failure – associated with high risk of bleeding
´ Thrombocytopenia
´ congestive splenomegaly (hypersplenism)
´ Immune-mediated shortened platelet lifespan (primary biliary
cirrhosis)
Coagulation disorders associated with liver
failure
´ Anatomic abnormalities
due to underlying liver
disease further promote
the occurrence of
hemorrhage
´ Dysfibrinogenemia -
impaired fibrin
polymerization
 Coagulation disorders associated with liver
failure
´ Laboratory evaluation
´ PT, aPTT, TT – prolonged
´ Thrombocytopenia
´ FDP – normal or slightly increased
´ Fibrinogenemia – diminished in fulminant hepatitis,
decompensated liver cirrhosis, advanced liver diseases, DIC
´ Dysfibrinogenemia – prolonged TT, normal fibrinogen & FDP
´ FVIII – normal or elevated
´ decreased with if superimposed DIC
´ FV – reduced level suggests hepatocyte failure
´ Normal FV but low FVII – suggest Vitamin K deficiency
Coagulation disorders associated with liver
failure

´ Treatment
´ FFP (5-10 or mg/kg) – to ensure 10-20% of normal levels
´ Do not correct clotting factors
´ Platelet concentrate
´ for counts 10,000-20,000/uL
´ <50,000/uL with ongoing bleed or before invasive procedure
´ Antifibrinolytic - avoided
Liver disease & thromboembolism
 Acquired inhibitors of coagulation
´ An autoimmune disease
´ Characterized by the presence of auto-antibody against a
specific clotting factor
´ 50% - no underlying disease identified
´ Autoimmune, malignancies, dermatologic diseases, pregnancy
´ FVIII – most common target
´ Inhibitors to prothrombin, FV, FIX, FX, FXI
 Acquired inhibitors of coagulation
´ FVIII – most common target
´ Acquired hemophilia A
´ Occurs predominantly in adults, pregnant or post partum women
´ Hemarthroses are rare
´ Retroperitoneal hemorrhages & life threatening bleeding – may
appear suddenly
´ Mortality – 8-22%
´ Prolonged aPTT, normal PT & TT
´ Bethesda assay – confirm the diagnosis
´ Responsive to immune suppression (steroid with cytotoxic
therapy)
 Acquired inhibitors of coagulation
´ Laboratory evaluation
´ aPTT, PT, TT – prolonged
´ fails to improve by transfusion of FFP or Vit K

´ Treatment
´ No established treatment guideline
´ Platelet transfusions – used as a source of FV replacement
´ Supplementation with FFP & Vitamin K
´ Recombinant FVIIa – limited use
Disorders of the vessel wall

´ Vessel wall is an integral part of hemostasis

Disorders of the vessel wall

´ Metabolic & inflammatory disorders

´ Immune complexes (viral antigens or virus) or complement
activation !Vascular endothelial damage ! increased vascular
permeability & localized hemorrhage
´ Acute febrile illnesses, scurvy, Cushing’s syndrome, monoclonal
gammopathies
´ Inherited disorder of the vessel wall
´ Inherited disorder of the connective tissue matrix or inherited
vascular abnormalities
´ Marfan’s & Ehlers-Danlos syndromes, Osler-Weber-Rendu
disease
Hemostasis

´ Refers to the finely regulated dynamic process of

maintaining fluidity of the blood, repair vascular injury, and
limiting blood loss while avoiding vessel occlusion and
inadequate perfusion of vital organs
´ Platelet, coagulation proteins & blood vessel wall play key
roles
Coagulation

´ The process by which thrombin is activated and soluble

plasma fibrinogen is converted into insoluble fibrin
Thrombosis
´ The obstruction of blood flow due to formation of clot ! tissue
anoxia & damage
´ Primarily involves the interplay of vessel wall, coagulation
proteins, & platelets
´ Venous thromboembolism – primary hypercoagulable states
reflecting defects in the proteins governing coagulation and/or
fibrinolysis or secondary hypercoagulable states involving
abnormalities of blood vessels and blood flow or stasis lead to
thrombosis
´ Arterial thrombosis – highly dependent on the state of the
vessel wall, the platelet and factors related to blood flow
Arterial thrombosis

´ Platelets and abnormalities of the vessel wall play a key role

in vessel occlusion
´ Major cause of morbidity & mortality
´ Myocardial infarction, thrombotic stroke
 Platelet
´ Platelet granules –
synthesized in
megakaryocytes before
thrombopoiesis
´ Contain prothrombotic,
proinflammatory &
antimicrobial mediators
´ 2 major types & distinguished
by their size, abundance &
content:
´ Alpha-granules
´ Platelet-dense granules
 Platelet

Alpha-granules Platelet-dense granules

Soluble coagulation protein Smaller

Adhesion molecules Less abundant
Growth factors Contain small molecules
Integrins Adenosine diphosphate (ADP)
Cytokines Serotonin (5-HT)
Inflammatory modulators

- Contain proteins that are important in the - Contain proteins that influence platelet
inflammatory response aggregation
Platelet activation & thrombosis
 Platelet activation & thrombosis

´ The stimulation of platelet

receptors triggers 2 specific
processes:
´ Activation of internal
signaling pathways that
lead to further platelet
activation & granule
release
´ The capacity of the platelet
to bind to other adhesive
proteins/platelets
 Platelet activation & thrombosis

´ G-coupled seven
transmembrane
receptor – found on
platelet & regulate
platelet functions
 Platelet activation & thrombosis

´ GPIIb/IIIa receptor –
serves as bidirectional
conduit
´ GPIIb/IIIa-mediated
signaling occurring after
the binding of fibrinogen
(outside-in)! intracellular
signaling that stabilizes
the platelet aggregate &
transforms platelet
aggregation from a
reversible to irreversible
process (inside-out)
Role of platelet & thrombosis in
inflammation
´ People are at a higher risk of myocardial infarction &
thrombotic stroke during acute infection
´ Increased interaction between platelets (homotypic
aggregates)
´ Increased interactions between platelets & leukocytes
(heterotypic aggregates)
Role of platelet & thrombosis in
inflammation
´ Platelets bind to
leukocytes ! increased
expression of
CD11b/CD18 on
leukocytes ! supports
interaction of leukocyte
with platelet
´ P-selectin induces the
expression of tissue
factor on monocytes !
promotes fibrin formation
Role of platelet & thrombosis in
inflammation
´ CD40L – trimeric
transmembrane protein of
the TNF family + CD40
receptor ! important
contributor to the
inflammatory process
leading to thrombosis &
atherosclerosis
 Role of platelet & thrombosis in
inflammation
´ Platelets contribute to the
pathophysiology & high
mortality rates of sepsis
´ Stimulation of platelet
TLR2, TLR3, TLR4
directly or indirectly
activates the platelet’s
thrombotic &
inflammatory responses
 Venous thrombosis

´ Stasis or states of
hypercoagulability plus the
initiation of the
coagulation process
influences the
development of venous
thrombosis
´ Primary forms:
´ Deep vein thrombosis
(DVT)
´ Pulmonary embolism
 Venous thrombosis

´ Antithrombotic factor also

regulate coagulation by limiting
the production of thrombin to
prevent perpetuation of
coagulation & thrombus
formation
´ Antithrombin
´ Tissue factor pathway inhibitor
´ Heparin cofactor II
´ Protein C/protein S
Fibrinolysis & thrombosis
 Distinction between arterial & venous thrombosis
Arterial thrombosis Venous thrombosis

Patho- Thrombosis is primarily promoted by Thrombosis is activated with the

physiology adhesion of platelets to an injured initiation of the coagulation
vessel & stimulated by exposed ECM cascade primarily due to exposure
of TF in a setting of stasis or
hypercoagulable states

Risk factors Age, obesity, cigarette smoking, DM, arterial HTN, hyperlipidemia, metabolic
syndrome, elevated plasma TAFI
Malignancy, acute, extremity
paresis, venous stasis,
immobilization, pregnancy, HRT,
OC use, FV Leiden & prothrombin
G20210A mutation
 Distinction between arterial & venous thrombosis

Arterial thrombi Venous thrombi

Are superimposed on disrupted Originate in the valve cusps of the deep vein
atherosclerotic plaque

Rich in platelets Predominantly composed of fibrin & trapped

RBCs

White thrombi Red thrombi

Antiplatelet agents are given to attenuate Anticoagulant is the mainstay of treatment
arterial thrombosis

In acute setting, use of anticoagulants & Fibrinolytic is used only in selected patients
fibrinolytics