PP of hematopoietic system I – etiopathogenesis of
disorders of primary and secondary hemostasis
Content
- Physiological primary plug formation and blood clotting
as a higly regulated process
- Virchow‘s triad
- Bleeding disorders (bleeding diathesis) due to
- disorders of primary hemostasis (thrombocytopenia and
thrombastenia)
- disorders of secondary hemostasis (hypocoagulation states)
- Hypercoagulation (thrombotic) disorders
- thrombosis and embolization in typical locations
Blood – haematocrit, plasma  serum, proteins, sedimentation
Factors keeping the blood fluidity
• physiologic blood clotting (= haemostasis) prevents the
blood loss
• primary
• secondary
• Virchow’s triad
• vessel wall (intact endothelium)
• blood (clotting factors in balance with anti-clotting and
fibrinolytic mechanisms)
• blood flow (preventing ptrolonged contact with verssel wall)
• alteration of any of the factors (or combination) leads to
• pathological blood clotting (= thrombosis)
• increased risk
• spontaneous
• examples: deep vein thrombsis (DVT), atherothrombosis
• event. subsequent occlusion by thrombus fragment =
embolization
Common causes of thrombosis
Hemostasis – phases
• (1) Arteriolar vasoconstriction occurs
immediately by the reflex mechanism of the
nervous system right after vascular injury,
which can be enhanced by endothelin, a potent
vasoconstrictor released from the endothelial
cells constituting the vessel wall.
• (2) Platelets bind to the von Willebrand factor
and adhere to the extracellular matrix at the
site of injury, after that, they change their
appearance (activation) and promote further
recruitment and aggregation of platelets by
releasing granules such as ADP and TxA2.
• (3) Tissue factor released from vascular
endothelial cells expresses the platelet
phospholipid complex. Through the coagulation
cascade, they eventually activate thrombin and
ultimately make the fibrin polymer to form a
clot/coagulum/thrombus.
• (4) During this period, the platelet plug contains
trapped neutrophils and RBCs in the blood
vessels, showing permanent plugs and
preventing further bleeding. In the absence of
vascular injury or complete thrombus
formation, the endothelial cells secrete t-PA
and thrombomodulin, which inhibit platelet
adhesion and aggregation, to exert
antithrombotic effects and fybrinolysis that
lead limitation of hemostasis.
Platelet formation  structure
• alpha granules - contain proteins
necessary for platelet adhesion
• vWF, fibrinogen and vitronectin contribute
to thrombus formation and stabilization
• angiogenic factors - VEGF, EGF and PDGF
• angiogenesis inhibitors - angiostatin,
thrombospondin and endostatin
• regulators of inflammation or cytokines platelet
factor 4 (PF4), CCL5 (RANTES), and
interleukin-8 (IL-8)
• dense granules - platelet activation and
recruitment and thrombus stabilization at
a site of injury
• ATP, ADP, serotonin, and calcium
• GPIIb-IIIa is expressed exclusively by
megakaryocytes and platelets and is
essential for both initiating and
propagating thrombus formation
Primary hemostasis
Mechanisms of platelet adhesion and aggregation: Erosion or rupture of an atherosclerotic plaque exposes the thrombogenic
subendothelial matrix proteins von Willebrand factor (vWF) and collagen. vWF binds to exposed collagen and uncoils, exposing
multiple binding sites for platelet glycoprotein (GP)Ib–IX–V. Under arterial shear stress, the capture of platelets is mediated by
interactions between GPIb and vWF (platelet tethering), which allows GPVI to bind to collagen. The binding of collagen to GPVI
results in platelet activation and the release of the soluble agonists ADP and thromboxane A2 (TxA2), leading to GPIIb/IIIa
activation via inside-out signalling. Activated GPIIb/IIIa changes conformation from the resting low-affinity state to a state of high
affinity for its major ligand, fibrinogen. GPIIb/IIIa bound to fibrinogen acts as a bridge for platelets to aggregate. The nascent
platelet thrombus is reinforced by the release of soluble agonists, such as ADP and TxA2. Thrombin generation is initiated by the
release of tissue factor from the plaque and occurs on the surface of highly activated (procoagulant) platelets, resulting in a fibrin
network that stabilizes the platelet thrombus.
• endothelium normally inhibits
haemostasis by secretion of inhibitors
of platelet aggregation and coagulation
• nitric oxide
• prostacyclin
• thrombomodulin
• heparansulfate
• tPA
• endothelial damage stimulates
platelets to adhere to vWf expressed
on exposed subendothelium by their
receptors (GPIb-IX)
• following platelet activation leads to
release of mediators from granules
• thromboxane, PAF, ADP, serotonin 
activation of more thrombocytes
(aggregation), vasoconstriction
• expression of integrins (GPIIb/IIIa) 
binding of fibrin and formation of
definitive clot
• thrombocytes participate in the
secondary haemostasis
• by releasing tissue fator and by formation of
thrombin on their surface (FIIa)
Primary platelet plug
• Platelet adhesion and aggregation:
• (A) Platelets normally circulate through the vasculature
in a nonadhesive state. Upon the detection of an
exposed subendothelial matrix, platelets are induced to
come into close contact with the vessel wall and roll,
then arrest, at the site of vessel injury. The process of
adhesion is orchestrated by the platelet adhesion
receptors GPVI and GPIb-IX-V. The release of soluble
agonists, such as ADP and thromboxane A2 (TxA2)
amplify platelet activation. Platelet adhesion and
activation, results in the formation of a platelet plug
(thrombus).
• (B) Platelet engagement with the blood vessel wall is
predominantly mediated by GPVI and GPIb-IX-V;
however, the platelet surface possesses receptors that
can engage matrix proteins. Additional involvement of
these other adhesion proteins, including integrins α2β1,
α5β1, and α6β1, which bind collagen, fibronectin, and
laminin, respectively, and αIIbβ3 that binds VWF and
fibrinogen, among others, help to stabilize the initial
attachment and facilitate platelet recruitment and
thrombus growth. Platelet activation occurs following
agonist binding to GPIb-IX-V and GPVI, integrin αIIbβ3,
FcγRIIa, and the G protein-coupled receptors for
serotonin (5-HT2A), ADP (P2Y1/12), epinephrine (α2A
adrenergic receptor), TxA2 (TP), and thrombin (PAR1).
Abbreviations: ADP, adenosine diphosphate; VWF, von
Willebrand factor; GP, glycoprotein.
Primary platelet plug
• Distinct steps of platelet adhesion, activation,
and aggregation at the activated
endothelium. (A) The initial adhesion of
platelets (tethering) is mediated by the
binding of the glycoprotein (GP)Ib-V–IX
receptor complex to the A1 domain of the
von Willebrand factor (VWF) on endothelial
cells. Additionally, binding to P-Selectin can
enhance platelet recruitment to the intact
vessel wall. (B) In a second step, interactions
between GPVI and collagen stabilize the
thrombus. Moreover, it comes to a cellular
activation with secretion of platelet agonists
(e.g., adenosine diphosphate, ADP) and
transformation of the GPIIb/IIIa receptors to
a state with high affinity. (C) The common
final pathway of the platelet activation via
the GPIIb/GPIIIa (integrin–fibrinogen)
pathway culminates in an irreversible platelet
aggregation and subsequent thrombus
growth.
endothelia platelets
bronchial
SMCs
membrane phospholipids
phospholipase A2 steroids
aspirin, NSAIDs
zileton
montelukast
selective
COX-2
inhibitors
Antiplatelet therapy
There is only 1 (2) way how to coagulate the
blood, but there are many ways how to bleed
Clotting factors
• named according to their chronological discovery
• initially Morawitz 1905
• the cascade/waterfall model in 1964
• model based on in vitro data!!
• all factors with the exception of TF (FIII) are present in the plasma
• in an inactive form (zymogens)
• only FVIIa normally circulates in small amounts in the blood
• majority of clotting factors (except TF and FVIII) are synthesized in liver
• FII, VII, IX a X are vit. K dependent
• substrate
• fibrinogen (FI)
• serine proteases
• activated FII, VII, IX, X, XI, XII and prekalikrein
• plasminogen, t-PA a u-PA
• cofactors (in tetrameric complexes)
• HMWK, FVIII and FV
Fibrinogen - fibrin
• 3 pairs of polypeptides ([A-α][B-β][γ])2 – 340kDa
• D – E – D domains
• thrombin (serine protease) cleaves fibrinopeptides A and B and
generates fibrin monomers (α-β-γ)2
• monomers spontaneously aggregate and form fibrin mesh
• fXIII (transglutaminase) further catalyses formation of cross-links
between fibrin polymers
• without fXIII (for example in hereditary deficiency) there is a unstable fragile
coagulum prone to bleeding
Hemostasis simply – old waterfall model
• The coagulation cascade/waterfall model has formed the basis for
our understanding of coagulation for almost the past one-half
century
• it provides a logical explanation of the clotting reactions in vitro
• in vitro laboratory studies that often used platelet-poor plasma
• prothrombin test [PT] and its international normalized ratio (INR)
scalefor extrinsic and activated partial thromboplastin time [aPTT]
test for intrinsic pathways were developed
• they measure the time it takes to form an in vitro fibrin clot after a blood
sample has been recalcified in the presence of appropriate reagents
• patients with specific deficiencies in the intrinsic arm of the
coagulation pathway - for example, of FXII, prekallikrein (PK) and
high-molecular-weight kininogen (HMWK) - have a prolonged aPTT
without exhibiting increased bleeding tendencies
• patients with deficiencies in other factors associated with the
intrinsic pathway—factor VIII (FVIII) and factor IX (FIX)—have a
serious bleeding tendency even when the extrinsic pathway is
functional
• conversely, patients with a deficiency in factor VII (FVII), an extrinsic
pathway factor, also have a bleeding diathesis, even when the
intrinsic pathway is not affected
• patients with deficiencies of factor X (FX) and factor V (FV), which
are common pathway factors, may have impaired hemostasis, and
patients deficient in factor XI (FXI) may have a bleeding diathesis
that is much less predictable
• Therefore, both pathways are interdependent in vivo!!!
• CELL-BASED MODEL OF COAGULATION
• the TF/FVIIa complex is the sole initiator of coagulation in vivo
primary (extrinsic)
pathway
accessory
(intrinsic) pathway
Tissue factor – coagulation and more
• TF–fViia complex formation on the surface of endothelial cells results in the activation of the
extrinsic coagulation cascade and/or Pars. The serine protease activity of the TF–fViia binary
complex associated with the plasma membrane initiates activation of downstream
coagulation cascades associated with coagulation factors (IX, X, prothrombin, and
fibrinogen). Otherwise, this protein complex cleaves the N-terminal end of PARs. PARs are
then activated via intramolecular binding between the newly created n-terminus and an
extracellular loop region of the receptors. activation of G-protein coupled receptors
subsequently activates downstream signalling cascades. Phosphorylation of the C-terminal
end of TF could also lead to association with Par2 in a coagulation-independent manner to
augment the signalling cascade
Hemostasis happens on blood cell surfaces – cell based model
• primary (formerly extrinsic) is fast, but less effective = INITIATION
• TF is a cell receptor for FVIIa
• TF + FVIIa + Ca + PL = extrinsic tenase complex
• amount of activated thrombin is small and insufficient to convert required
amount of fibrinogen, but effective to activate FXI (and FIX and cofactors
FVIII and FV) and thrombocytes
• moreover, TF is quickly inactivated by TF inhibitor (TFPI)
• following the TF blockade by TFPI the accessory (formerly
intrinsic) pathway, that is longer but more effective =
AMPLIFICATION and PROPAGATION
• activation of FXI, FIX, FVIII and FV by thrombin
• IXa + VIIIa + Ca + PL = intrinsic tenase that effectively activates FX
• FXa in a complex with FVa, Ca and PL (= prothrombinase) effectively
converts prothrombin to FIIa and the cleaving the fibrinogen
• negatively charged phospholipids (PL) necessary for the
formations of complexes are provided by blood cells, namely
platelets and monocytes
• role of HMWK, factors XII and XI (in a contact with negatively charged
surfaces e.g. on.
• exposed subendothelial collagen in vessels
• lipoproteins (chylomicrons, VLDL)
• bacterial wall
• is less clear in vivo (compared to the old „waterfall“ theory)
• deficiencies of HMWK, FXII and to some extent FXI do not lead to bleeding
+ VIIIa + Ca + PL
Shannon M. Bates. Circulation. Coagulation Assays, Volume: 112, Issue: 4, Pages: e53-e60, DOI: (10.1161/CIRCULATIONAHA.104.478222)
Coagulation pathways
• Coagulation is initiated by extrinsic tenase,
which forms when factor VIIa binds to tissue
factor. Extrinsic tenase activates factors IX
and X. In the presence of calcium, factor IXa
binds to negatively charged phospholipid
surfaces where it interacts with factor VIIIa to
form intrinsic tenase, a complex that
efficiently activates factor X. Factor Xa binds
to factor Va on negatively charged
phospholipid surfaces to form
prothrombinase, the complex that activates
prothrombin to thrombin. Thrombin then
converts fibrinogen to fibrin. Activated
platelets or monocytes provide negatively
charged phospholipid surfaces on which
these clotting reactions occur.
Coagulation tests
bleeding time (in vivo) – primary hemostasis
(PLT function)
Loss of blood is a life threatening event, but the
longer absence of perfusion as well
• Regulation of blood clotting
• (1) velocity of blood flow
• (2) intact endothelium
• non-sticky
• vasodilation (NO, PGI2)
• heparan sulfate (neutralizes serine proteases)
• thrombomodulin (neutralizes thrombin)
• t-PA (fibrinolysis)
• (2) concentration of inhibitory factors
• (a) control on the levels of thrombin
• heparin
• antithrombin III (and heparan sulfate)
• inhibits thrombin and also IX, X, XI and XII
• a2-macroglobulin
• heparin cofactor II
• a1-antitrypsin
• (b) control on the level of factor Xa (inactivation of FVIII a V)
• protein C + thrombomodulin
• protein S
• (3) activity of fibrinolysis
Why blood stasis may lead to thrombus (Virchow)
• Regulation of fibrin clotting by flow via the factor
VII activation by factor Xa. The diagram illustrates
the mechanisms controlling initiation of coagulation
in the presence of flow. Factor VIIa initially present
in plasma binds to TF and activates factor X; it is
also inhibits by TFPI. Factor Xa can activate TFbound
factor VII in a positive feedback manner. In
the absence of flow, both inhibition by TFPI and
activation by factor Xa are not significant, because
high concentrations of TF present on fibroblast
rapidly bind factor VIIa; they do not need additional
factor VII activation and are not particularly
sensitive to factor VIIa-TF complex inhibition. When
blood flow is present, factor Xa is rapidly removed,
and the rate of factor X production becomes
insufficient to create fibrin clot (factor VIIa-TF
complex being inhibited by TFPI). This is when
factor Xa-dependent feedback becomes important:
factor Xa activates factor VII and increases its own
production, counteracting the effects of flow. At
higher shear rates, this feedback is insufficient, and
factor Xa production is strongly inhibited. Thus,
inhibition of factor VIIa-TF complex by TFPI and
factor VII activation by factor Xa combine to create
a threshold-like response of the system in flow:
rapid clotting at low shear rates and almost no
thrombus formation at higher shear rates.
Fibrinolytic system
• plasmin (serine protease) circulates as a
inactive proenzyme (plasminogen)
• free plasmin vividly inhibited by α2-
antiplasmine
• activation of plasminogen by tissue
plasminogen activator (t-PA) (from
endothelium) and urokinase u-PA (from
epithelia) to plasmin
• degradation of fibrin to fibrin-degradation
products
• one of which are a D-dimers used in
diagnostics of thrombosis
• activity of tPA inhibited by PAI-1
• PAI-1 is an acute phase reactant and factor
increased in obesity
Hemostasis disorders
• (A) hypocoagulation states (bleeding diathesis)
• defects of primary haemostasis
• vessel wall diseases
• thrombocytopenia
• thrombocytopatia/thrombasthenia
• incl. von Willebrand disease
• defects of secondary haemostasis (coagulopathies)
• hereditary
• haemophilia A and B
• von Willebrand disease
• acquired
• malnutrition, chronic liver disease etc.
• (B) hypercoagulable states (thrombophilia)
• hereditary
• activated protein C resistance (APCR)
• acquired
• (C) combined
• syndrome of disseminated intravascular coagulation (DIC)
HYPO-COAGULATION DISORDERS (BLEEDING
DIATHESIS)
Skin and mucosal bleeding in defective 1-y hemostasis
• (1) vasculopathies
• inborn hereditary
• telengiectasia hereditaria (m. Rendu-Osler)
• thinning of vessel wall  telengiectasias (skin, mucosas, lungs, urogenital tract)
• Ehlers-Danlos and Marfan syndrome
• defective structure of connective tissue (collagen or elastin)
• acquired
• senile purpura
• bacterial toxins (measles, scarlet fever)
• vit. C deficiency (scorbutic)
• immune complexes (Henoch-Schönlein purpura)
• (2) thrombocytopenia
• (3) thrombocytopathia/thrombasthenia
• (4) von Willebrand disease
Defects of primary hemostasis
• manifestation:
• skin: petechiae (1-2mm), purpura (>2mm), ecchymosis (>1cm) – easy bruising (worse in alcoholic
malnutrition
• mucosal membranes: epistaxis, bleeding from gums or GIT, haematuria, menorrhagia, haemoptysis
• intracranial bleeding only in very severe disorders (e.g. intraspinal hematoma after lumbar
punction)
Menorrhagia
Thrombocytopenia - platelet count
• reference range 150,000 –
400,000/L
• clinically significant values (
2SD)
• bleeding <50,000/L + symptoms
• thrombocythemia >750,000/L
Thrombocytosis (= thrombocythemia) =  PLT count
• clinically insignificant unless PLT >750,000/L
• primary (essential) – rare
• one of the forms of myeloproliferative disorders
(disease of the elderly)
• essential thrombocythemia or polycythaemia vera
(clonal proliferation)
• secondary (reactive) – common
• 100 in children
• 80 in adults
• generally due to
•  TPO (thrombopoetin)
• ( IL-6  TPO)
•  EPO (mimics the effect of TPO)
• iron deficiency, bleeding, haemolytic anaemia, malignancy
(anemia)
•  IL-6 (inflammation)
• infection, malignancy
bleeding due
to PLT
consumption in
microthrombi
Thrombocytopenia
• PLT count normally 150 – 400 000/μl (1.5–41011/l)
• in circulation 8-10 days
• aetiology - primary or secondary
• low production
• aplastic anaemia (pancytopenia)
• myelodysplastic syndrome
• myelofibrosis
• B12 a/or pholate deficiency
• liver disease ( TPO)
• destruction/consumption/splenic sequestration
• autoimune - idiopathic thrombocytopenic purpura (ITP)
• AIHA + ITP = Evans syndrome
• drug-induced (valproate, methotrexate, …)
• SLE (systemic lupus erythemoatodes)
• APS (anti-phospholipid syndrome)
• hypersplenism
• high consumption
• DIC
• thrombotic thrombocytopenic purpura (TTP)
• HELLP (pregnancy) = hypertension, elevated liver enzymes and low platelets
• hemolytic-uremic syndrome (HUS)
• dilutional
• mostly benign, e.g. pregnancy (volume expansion)
• bleeding in trombocytopenia
• superficial – skin and mucosla mostly
• <50 000/μl – mild risk of bleeding
• <20 000/μl – significant risk of bleeding
• <5 000/μl – extremely high risk of bleeding
bleeding time
Thrombocytopathia = impaired PLT function
• abnormal adhesion or aggregation
• Bernard-Soulier syndrome
• receptor GPIb-IX defect
• Glanzmann thrombastenia
• receptor GPIIb-IIIa defect
• von Willebrand disease
• vWf deficiency
• abnormal degranulation
• Heřmansky-Pudlák syndrome
• Chédiak-Higashi syndrome
von Willebrand disease
• Von Willebrand Disease (VWD) is a genetic disorder caused by
missing or defective von Willebrand factor (VWF), which help form
a platelet plug during the clotting process
• deposited in blood vessel walls and after exposure binds to platelets
(alpha granules) - abnormal adhesion of platelets (primary hemostasis)
• vWf also binds FVIII in plasma (otherwise unstable and degraded
quickly)  defective secondary hemostasis
• The most common inborn disease of coagulation
• The gene for von Willebrand factor is on one of the autosomes,
chromosome 12
• since it is not on the sex chromosome (unlike hemophilia), it occurs
equally in men and women
• if only one parent has a dominant inheritance type of VWD, with each birth
there is a 50% chance of having a child (boy or girl) who inherits the VWD
mutation
• a 50% chance of having a child (boy or girl) who does not inherit the VWD
mutation
• several types of vW disease
• type 1 (~75%) – low concentration of vWf
• symptoms are usually mild
• type 2 (~20%) – normal concentration of non-functional vWf
• four subtypes: type 2A, type 2B, type 2M and type 2N, depending on the
presence and behavior of multimers
• binding to platelets (type 2A)
• binding to collagen of subendothelial layer (type 2B)
• transport of fVIII (type 2N)
• symptoms are mild to moderate
• type 3 – absolute deficit vWf (homozygotes)
• symptoms are typically severe, and include spontaneous bleeding episodes,
often into their joints and muscles
Many subtypes of vWD
Quantitative defects of von Willebrand factor, as seen in von
Willebrand disease types 1 & 3. In the classic presentation, type 1
VWD sees a decrease in VWF:Ag, VWF:RCo, and FVIII:C, and
multimer levels are normal. Type 3 VWD presents with the same
decreases, but to a much greater degree, and multimers are
absent. Types 1 & 3 both show decreased secretion. Type 1C
presents similar decreases to type 1, but shows an increase in the
ratio of VWFpp to VWF:Ag and an abnormally high quantity of
multimers, as well as increased clearance.
Qualitative defects of von Willebrand factor, as seen in von
Willebrand disease type 2. Like types 1 & 3, all forms of type 2 VWD
present with a decrease in VWF:Ag, VWF:RCo, and FVIII:C. In type
2A, there is decreased secretion of VWF and an increased
susceptibility to ADAMTS13 and abnormal multimers. Type 2B
presents with increased binding to platelets, abnormal multimer
count, and enhanced LD RIPA. Type 2M shows decreased binding to
platelets and multimer levels are normal, while type 2N presents
with decreased binding to FVIII and normal multimers as well.
Defects of secondary haemostasis
• typically bleeding to the tissues (hematomas), e.g. joints, muscles, brain,
retroperitoneal space
• no petechias or purpura
• (A) inborn disorders
• haemophilia A (Xq-chromosome linked) – defect of fVIII
• fVIII serves as a co-factor of activation of fX to fXa in the reaction catalysed by fIXa
(intrinsic tenase)
• decrease of concentration up to 25% of normal values does not cause coagulation
disorder, decline to 25-1% mild form, <1% severe form
• >150 point mutations in fVIII gene – large phenotypic variability!!!
• eventually inhibitor of FVIII is responsible
• prevalence in males 1:5,000 to 1:10,000
• haemophilia B (Xq-chromosome linked) – defect of fIX
• prevalence 10x lower than haemophilia A
• >300 mutations in fIX gene (85% point mutations, 3% short deletions and 12% large
deletions)
• defects of other factors
• rare, mostly autosomal recessive, clinically manifested only when severe deficit
• afibrinogenemia (defect fI)
• haemophilia C (defect of fXI) – Askenazy Jews
• (B) acquired disorders
• liver insufficiency
• vitamin K deficit (lipid malabsorption)
• DIC
Hemophilia A and B genetics
Hemophilia in females – parents or chromosomal lyonization
• An early female embryo chooses, at random, to inactivate paternal
X chromosomes (blue, normal) in some cells and maternal ones
(red, with a hemophilia A mutation) in others. On average (middle
right) half the cells retain the ability to make factor VIII normally
and half do not. Occasionally, most cells retain the ability to make
factor VIII (top right) or lose that ability (bottom right).
DIC (consumption coagulopathy)
• initially hypecoagulation (thrombotic state), later consumption of coagulation factors
(bleeding)
• coagulation becomes non-limited in space and is not a primary reaction to injury
• pathogenesis
• circulation doesn’t normally contain TF!!!
• nor endothelial neither blood corpuscles do not produce it on their surface
• some pathologic situations lead to activation of factor VII by TF (and subsequently of
extrinsic pathway) - pathological sources of TF:
• tissue cells – e.g. fetal cells during birth, extensive traumas, spreading of cancer cells etc.
• pathological blood elements expressing TF – e.g. myelo- and lymphoproliferative diseases
• pathologically activated endothelium and monocytes stimulated by endotoxin during sepsis to produce TF
• TF from the cytoplasm of erythrocytes during haemolysis
• consequences
• 1. phase - microthrombi in micro-circulation
• ischemia or even gangrene
• 2. phase - hypo- to afibrinogenemia, thrombocytopenia
• bleeding to organs
• pathologic fibrinolysis
HYPERCOAGULATION STATES
(THROMBOPHILIA)
Hypercoagulation states
• increased risk or spontaneous and often recurrent
venous thromboses and thrombembolisms (lung
typically), event. pregnancy complications,
infertility
• (A) inherited thrombophilias
• (1) defects of coagulation inhibitors
• AT III deficiency (AR)
• protein C or S deficiency (AD)
• activated protein C resistance (APCR)
• activated protein C (with protein S as a cofactor) degrades
fVa and fVIIIa and limits coagulation
• mutated fV does not respond to activated protein C - most
common inborn genet. abnormality (“Leiden” mutation of
fV)
• mutation of prothrombin gene (promotor  quantitative
effect)
• hyperhomocysteinemia (mutation in MTHFR gene)
• antiphospholipid syndrome
• anti-cardiolipin antibodies, lupus anticoagulans etc.
• hypehomocysteinemia
• (2) defects of fibrinolysis
• LP(a)
•  PAI-1 (promotor  quantitative effect)
Hypercoagulation states
• (B) acquired thrombophilias
• (1) clin. situations and complications of therapy
• immobilisation
• hyperoestrogenic states
• pregnancy
• oral contraception
• HRT
• (2) pathologic situations
• atherosclerosis
• obesity ( PAI-1)
• hyperviscous syndromes
• polycythemia vera, thrombocythemia, sec.
polyglobulia, gamapatias)
• tumours
• heart failure
• sepsis
• hyperlipidemias
• nephrotic syndrome
• venous insufficiency
• hypehomocysteinemia
Atherosclerosis x coagulation
Hyperhomocysteinemia (HHcy)
• homocystein is an intermediate product in the methionine cycle
• either further metabolised to cysteine
• or remethylated back to methionine (in the folate cycle)
• several enzymes and their cofactors are needed (vitamins B, folic acid)
• the reasons for abnormal metabolism of homocysteine and subsequent
HHcy can be genetic or nutritional or both
• mutation in genes encoding enzymes
• deficient intake of vitamin B6, B12 and folic acid
• HHcy = pathologic increase of plasm. concentrations of homocysteine
• Hhcy is an independent risk factor of atherosclerosis and
thrombembolism, fertility disorders and some congenital defects and
neurological abnormalities (cleft spine)
• homocysteine induces endothelial dysfunction and initiates apoptosis
• (A) monogenic HHcy
• deficit of cystathionin--synthase (in homozygotes) leads to extreme
elevation of plasma Hc
• prematured atherosclerosis
• rare disease
• (B) mild HHcy
• polymorphism in gene encoding enzyme methylen tetrahydrofolate
reductase (MTHFR)
Homocysteine metabolic pathways
• Dietary methionine is converted to the methyl donor Sadenosylmethionine
(SAM) and is demethylated to Sadenosylhomocysteine
(SAH) and homocysteine. In the
transsulfuration pathway, homocysteine is converted to
cystathionine by the enzyme cystathionine -synthase
(CBS) and the cofactor vitamin B6 (pyridoxyl
phosphate). Once formed from cystathionine, cysteine
can be utilized in a number of cellular functions,
including protein synthesis and glutathione (GSH)
production. Homocysteine can also be remethylated
through the folate cycle. This pathway requires the
enzyme methionine synthase (MS) and vitamin B12 as
well as the enzyme 5,10-methylenetetrahydrofolate
reductase (MTHFR) and folic acid, which enters the
cycle as tetrahydrofolate (THF). In liver and kidney,
homocysteine is also remethylated by the enzyme
betaine homocysteine methyltransferase (BHMT),
which transfers a methyl group to homocysteine via
demethylation of betaine to dimethylglycine (DMG)
Deep vein thrombosis
Pulmonary embolism
Superficial vein thrombosis