Download Hemostasis

Hematology Pathophysiology: Platelets, Blood Coagulation and Hemostasis (Gabali)
PLATELETS:

Production of Platelets:
Basics: derived from cytoplasmic fragmentation of BM megakaryocytes (small, NON-NUCLEATED discs)
o Immature megakaryocytes (small, basophilic cytoplasm, less granules, less nuclear lobulation) must
transform into mature megakaryocytes (larger, less basophilic cytoplasm, more granules, more nuclear
lobulation)

Megakaryocytes undergo endomitotic synchronous nuclear replication (without separating)
to form a hyperlobulated nucleus

Granules appear in cytoplasm of megakaryocyte
o Cytoplasm fragments to form platelets (each megakaryocyte forms 1000-4000 platelets)
o This differentiation process takes ~10 days
Regulation: entire process is regulated by THROMBOPOIETIN
o Glycoprotein hormone produced by the liver and kidneys

Therefore, decreased in liver and kidney disease (may present with mild thrombocytopenia)
o Results in proliferation and maturation of MEGAKARYOCYTES (not platelets themselves), which then
fragment into platelets
Normal Values:
o Life span of platelet is 7-10 days
o Normal platelet count is 150,000-450,000/uL(mm3)

Platelet Granules:
Dense Granules:
o Number: 2-7 per platelet
o Content:

ADP and ATP

Serotonin

Ca++

Mg++

Cyclooxygenase
Alpha Granules:
o Number: 50-70 per platelet
o Content:

PDGF

PF4

HMWK

Fibronectin

Thrombospondin

Factor V

vWF

Fibrinogen
Lysosomal Granules:
o Content: phagocytosed debris

Role of Platelets in Hemostasis:
Hemostasis (In General): function is to keep blood within a damaged blood vessel
o Vasoconstriction
o Platelet plug formation
o Clot formation
o Dissolution of the clot
Main Function of Platelets: formation of PLATELET PLUG
o Occurs in response to vascular injury
o Occurs via 3 steps- adhesion, activation (secretion) and aggregation
PRIMARY HEMOSTASIS- FORMATION OF THE PLATELET PLUG:

Transient Vasoconstriction:
Mediated by:
o Reflex neural stimulation
o Endothelin release from endothelial cells



Platelet Adhesion:
Basics: occurs due to the exposure of the subendothelial collagen due to vascular damage
o von Willebrand Factor (vWF): monomer composed of 2813 amino acids

Monomers bind head-to-head and tail-to-tail

Produced in megakaryocytes (stored in alpha granules) and endothelium (stored in WeibelPalade bodies)

Has receptors for:
 Collagen* (important for platelet adhesion)
 Factor VIII (involved in transport of FVIII)
 GPIb (on platelet)
 GPIIb/IIIa (on platelet; also binds fibrinogen)
Process:
o Platelet adheres to exposed subendothelial collagen by one of 2 mechanisms:

Indirectly using vWF, which the platelet binds using the GPIb/V/IX receptor
 vWF binds exposed subendothelial collagen and then platelet binds vWF

Directly via platelet receptor GPIa/IIa (in LOW SHEER STRESS conditions)
 Platelet binds directly to subendothelial collagen
Result:
o Single layer of platelets attached to subendothelium and covering the site of injury
Platelet Activation:
Basics: once adhesion occurs, platelets become activated, changing their shape and releasing their granules
o Changes shape from disk to a sphere with extended pseudopodia
o Release of granules results in release of various mediators
Release of Granule Contents:
o ADP: promotes the exposure of GPIIb/IIIa receptor on platelets (required for platelet aggregation)

Pathoma concept*
o Arachadonic Acid + COX: leads to the formation of TXA2 (potent platelet aggregator)
o Other Substances Released:

Serotonin

Fibrinogen (required for aggregation; also found in the plasma)*

PF4

Lysosomal enzymes
Platelet Aggregation:
Basics: platelets aggregate to the site of injury via expression of GPIIb/IIIa
o Aggregation promoted by ADP and TXA2
Process:
o Fibrinogen is used as a linking molecule (binds GPIIb/IIIa on 2 separate platelets, linking them together)

Pg. 179 of the notes also shows vWF being used as a linking molecule, but is not mentioned
in the notes (could use either GPIb or GPIIb/IIIa receptor)*
o ADP causes platelets to swell and helps them stick together

Presumably due to increased GPIIb/IIIa expression? (Pathoma)

As they stick together, more ADP is released  (+) feedback system
o Overall end result is the formation of a platelet plug

Weak and needs to be stabilized through the coagulation cascade
Defects in Platelet Aggregation: to be discussed later*
o Glanzmann’s Thrombasthemia (GPIIb/IIIa deficiency)
o Von Willebrand’s Disease (vWF deficiency)
o Bernard-Soulier Syndrome (GPIb deficiency)
SECONDARY HEMOSTASIS- STABILIZATION OF THE PLATELET PLUG (COAGULATION CASCADE):

Coagulation Cascade:
Overall Result: leads to the generation of thrombin, which converts fibrinogen to fibrin
o Fibrin incorporates into platelet aggregates at site of injury
o Stabilizes platelet plug and converts it into a firm clot
Intrinsic Pathway:
o Factors: HMWK, prekallikrein, XII, XI, IX, VIII

FVIII is a cofactor for IXa in converting XXa
o Test: PTT

-




Note: while deficiencies in factor XII, HMWK and prekalikrein will lead to abnormally
increased PTT, they do NOT result in bleeding
Extrinsic Pathway:
o Factors: Tissue Factor (FIII), VII

TF called tissue thromboplastin in Pathoma

TF exposed via endothelial damage and binds FVII, activating it (VIIa)

TF/VIIa is also known as ninase and tenase
 VIIa converts XXa (tenase)
 VIIa also crosses over to intrinsic pathway to convert XI  XIa (ninase- misnomer
since it is actually converting FXI)
o Test: PT
Common Pathway:
o Factors: X, V, II (prothrombin), I (fibrinogen)

FV is a cofactor for Xa in converting prothrombin  thrombin
o Test: PT, PTT
Role of Thrombin:
Thrombin has 5 activities in the coagulation cascade:
o Converts fibrinogen  fibrin + fibrinopeptides A and B

Fibrin assembles into NON-crosslinked lattice initially (requires XIIIa for cross-linking)
o Activates factor V  Va
o Activates factor VIII  VIIIa
o Activates factor XI  XIa (POSITIVE FEEDBACK LOOP)
o Activates factor XIII  XIIIa (fibrin stabilizing factor- allows for cross-linking of fibrin lattice)
Production of Clotting Factors:
General: coagulation cascade factors are produced in the liver (in general) in an INACTIVE state
o Activation: requires 3 things

Exposure to an activating substance (ie. TF activates FVII in extrinsic pathway)

Phospholipid surface of the platelet

Calcium (released from dense granules of the platelet)
Factors Produced in the Liver:
o All factors (including fibrinogen, factor VIII and vWF)
Factors Produced in the Endothelium:
o vWF (stored in Weibel Palade bodies)
o Factor VIII
Factors Produced in the Megakaryocyte:
o vWF (stored in alpha granules)
o Fibrinogen (stored in alpha granules)
o Factors V? (content of alpha granule- posted on BB)
Role of Vitamin K:
Function: responsible for carboxylation of gamma carbon in vitamin K dependent factors
Vitamin K Dependent Factors: II, VII, IX, X, C, S
Natural Anticoagulants:
Tissue Factor Pathway Inhibitor (TFPI):
o Inhibits: VIIa/TF complex (ninase and tenase)
o Release: released from damaged tissue
o Function: only able to block coagulation cascade in the absence of thrombin

When thrombin is still present, positive feedback on FXI is stronger than the inhibition from
the VIIa/TF complex

Once thrombin is no longer present, TFPI can block the pathway all together
Antithrombin III:
o Inhibits: IIa, IXa and Xa
o Function: normally binds heparin-like products secreted by the endothelial cells (or heparin itself, if
being administered) to inhibit the above factors

ATIII can inhibit without the help of these heparin-like products, but it is much faster with
them (Pathoma)
Proteins C and S:
o Inhibits: Va, VIIIa, TPAI (inhibition promotes fibrinolysis)
o

Activation of Protein C: thrombomodulin released from the endothelium redirects thrombin to
activate protein C (Pathoma)
Normal Fibrinolysis:
Fibrinolysis: NORMAL response to vascular injury
Process:
o Fibrin  fibrin split products via PLASMIN

Fibrin split products include D-dimers and Fragment E
 Note that the presence of D-dimers indicates that the entire coagulation cascade
has been activated (and that it has come to completion)
o Plasmin is formed from plasminogen in the presence of tPA (tissue plasminogen activator, a serine
protease)
LABORATORY TESTS OF COAGULATION:

Tests to Assess Platelets:
Platelet Count:
o Thrombocytopenia: <150,000
o Thrombocytosis: >450,000
Mean Platelet Volume (MPV):
o Varies inversely with platelet count (ie. decreased counts result in increased MPV)
o Due to the fact that megakaryocytes have less time to fragment when trying to make up for low counts
Tests of Platelet Function: these are NOT routine tests (need to specifically request them)*
o Agonist-Induced Platelet Aggregation:

Method: addition of aggregating agent to platelet-rich plasma with subsequent
measurement of optical density of the tube
 If the platelets are aggregating normally, more light will pass through the tube
resulting in a low optical density
 Suspected defect detected depends on the agonist that is used to promote
aggregation

Different Agonists:
 ADP/EPI/Collagen/TXA2: aggregate platelets through GPIIb/IIIa and fibrinogen
o Therefore, if one of these agonists is added and the platelets do not
respond with aggregation, there is an issue with GPIIb/IIIa or fibrinogen
 Ristocetin: aggregates platelets through GPIb and vWF
o Therefore, if ristocetin is added and the platelets do not respond with
aggregation, there is a problem with GPIb or vWF
o Note that ristocetin is an Abx that is no longer used because it causes
platelet aggregation

Phases of Platelet Aggregation in Response to ADP (Figure on pg.187): as measured by
changes in optical density
 Initial increase in OD: due to increase/change in platelet size
 First decrease in OD: first phase of aggregation due to ADP release from granules
 Plateau in OD: because platelet has consumed all the granules that were
preformed (needs to synthesize more)
 Second decrease in OD: second phase of aggregation due to release of newly
synthesized ADP
o Bleeding Time: not really used anymore*

Test for Platelet Adhesion (Mainly): based on making a standard incision and recording time
to bleeding cessation with blot and filter paper every 30s
 Bleeding normally stops in 3-8 minutes

Cons to Use:
 Needs to be performed by trained personnel (liability issues)
 Poor predictor of bleeding during surgery
o Platelet Function Analyzer (PFA-100): replaced bleeding time*

Basics: tests adhesion and aggregation in response to agonists
 Cartridges contain either collagen + EPI or collagen + ADP
o Collagen tests adhesion
o EPI/ADP tests aggregation
 PFA-100 machine measures the time needed for occlusion of the cartridge

Use:



Determine if a patient is taking ASA or another platelet inhibitor
Determine if a patient is responding to therapy with ASA or another platelet
inhibitor
Tests to Assess Clotting Factors:
Prothrombin Time (PT)- Extrinsic and Common Pathways:
o Factors Tested: I, II, V, X (common), VII (extrinsic)
o Method: TF + thromboplastin (XI) + Ca + citrated plasma

Normal time is 10-14s

Critically dependent on the characteristics of the thromboplastin used in the assay

PTs vary between laboratories, and therefore the INR has been established to standardize PT
results between different labs
o Use:

Standard test for monitoring warfarin therapy (sensitive to vitamin K dependent factors II, VII
and X- not IX)
o Causes of Prolonged PT:

Liver disease (decreased clotting factor production)

Vitamin K antagonists (ie. Warfarin)

Heparin (in high concentrations)
 Better tested by PTT

Fibrin and fibrinogen degradation products

Lupus anticoagulant (if in increased concentration)
 Better tested by PTT
Partial Thromboplastin Time (PTT)- Intrinsic and Common Pathways:
o Factors Tested: I, II, V, X (common), XII, XI, IX, VII (intrinsic)
o Method: phospholipid + surface activator + Ca + citrated plasma

Normal time is 30-40s
o Use:

Monitoring heparin therapy

Monitoring factor replacement therapy in patients with hemophilia

Screening test for detection of coagulation inhibitors (ie. lupus anticoagulant)
o Causes of Prolonged PTT:

Heparin (inhibits Xa and IIa)

Vitamin K antagonists (in high doses)
 Better tested by PT

Fibrin and fibrinogen degradation products

Lupus anticoagulant
Mixing Study: done if prolonged PTT*
o Method: mixture of normal and patients plasma (50:50 mix) and check for correction of PTT

If PTT corrects by >50% of the difference between PTT of normal and patient plasma, it
indicates a deficiency in a clotting factor

If PTT does NOT correct, it suggests a factor inhibitor
 Inhibitor of a specific factor, OR
 Non-specific inhibitor (ie. lupus anticoagulant)
o Use: distinction between factor deficiency and factor inhibitor
Thrombin Time (TT): done if prolonged PTT*
o Method:

Diluted bovine thrombin + citrated plasma

Normal time is 10-15s
o Use: functional test of FIBRIN generation
o Causes of Prolonged TT:

Congenital:
 Afibrinogenemia
 Hypofibrinogenemia
 Dysfibrinogenemia (dysfunctional fibrinogen)

Acquired:
 Hypofibrinogenemia (liver disease, DIC, thrombolytic therapy)
 Dysfibrinogenemia (liver disease, hepatic malignancy)

Others:
 Fibrin degradation products
 Heparin
 Anti-thrombin antibodies
HEMOSTATIC DISORDERS:

General:
Abnormal bleeding may result from:
o Vascular disorders
o Quantitative or qualitative defective platelet function
o Defective coagulation

Vascular Disorders:
Basics:
o Characteristics:

Easy bruising

Spontaneous bleeding from small vessels
o Underlying Abnormality Occurs in:

Vessels, OR

Perivascular connective tissue
Inherited Causes:
o Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome):

Inheritance: autosomal dominant

Description: development of telangiectasias (dilated microvascular swellings)
 Appear during childhood and increase in number in adulthood
 Develop in:
o Skin
o Mucous membranes
o Internal organs (risk of recurrent GI hemorrhage with IDA- common
presentation)

Treatment:
 Laser
 Embolization
 Estrogen therapy? (seems counter intuitive since estrogen causes telangiectasiaasked on BB)
o Ehlers-Danlos Syndrome:

Inheritance: most forms are autosomal dominant

Description: results in collagen abnormalities

Clinical Presentation:
 Purpura
 Hyperextensibility of the joints
 Dissecting aneurysms
Acquired Causes:
o Scurvy: vitamin C deficiency  defective collagen

Present with:
 Ecchymoses
 Mucocutaneous bleeding
o Senile Purpura: caused by atrophy of supporting tissue of cutaneous blood vessels
o Purpura associated with Infection: vascular damage due to immune complex formation

Bacterial or viral (measles, dengue fever, meningococcal septicemia)
o Henoch-Schonlein Purpura: IgA mediated vasculitis in children (self-limiting)

Occurs after an acute infection (usually URI)

Characterized by purpuric rash

Need to watch for renal failure (can get IgA nephropathy)

Platelet Disorders:
Thrombocytopenias (QUANTITATIVE):
o Definition: platelet count <150,000/uL

In general, bleeding is not a problem until platelet count <50,000/uL + surgery/trauma

Spontaneous bleeding may occur with platelet counts of 5000-20,000/uL
o
Causes:

Bone Marrow Failure:
 Aplastic anemia
 Chemotherapy
 Irradiation

Neoplasms:
 Leukemia

Infections:
 Many of the thrombocytopenias caused by infections are immune mediated, via a
molecular mimicry process

Post Transfusion Purpura:
 Thrombocytopenia 10 days after transfusion
 Due to Abs in the recipient against HPA-1a on transfused (donor) platelets

Drug Induced Thrombocytopenia:
 Quinine
 Quinidine
 Heparin (HIT)

Immune Thrombocytopenic Purpura (ITP): most common cause of thrombocytopenia in
children AND adults*
 Cause: increased destruction of platelets due to autoimmune production of IgG
against platelet antigens (destruction of Ab coated platelets occurs in the spleen)
o Note that Pathoma states that the Abs are produced by the splenic
macrophages; therefore, source of Ab AND site of destruction is the
spleen
 Two Forms:
o Chronic Form: seen mostly in ADULTS

Commonly women of child-bearing age (15-50)

Usually idiopathic

May also be seen with:
 Autoimmune disease (SLE, AIHA)
 Infection (HIV)
 Malignancy (CLL)

AutoAbs to platelets result in early removal (shortened life span
of platelet)
o Acute Form: seen mostly in CHILDREN

~75% follow an infection or a vaccination

Result of NON-SPECIFIC immune complex attachments

Self-limited (usually results in spontaneous remission)
 Lab Values (Pathoma):
o Decreased platelet count
o Normal PT/PTT (coagulation cascade not affected)
o Increased megakaryocytes on BM biopsy

Thrombotic Thrombocytopenic Purpura (TTP):
 Cause: deficiency of a metalloproteinase (ADAMTS13) that normally breaks down
high molecular weight vWF
o Can be an inherited deficiency in the enzyme, OR
o An acquired autoAb to ADAMTS13 (Pathoma- this is the most common)
 Result: large, uncleaved monomers lead to abnormal platelet adhesion and
aggregation  microthrombi
 Characteristics:
o Fever
o Thrombocytopenia
o Microangiopathic hemolytic anemia (due to microthrombi)
o Uremia (due to renal problems as a result of thrombi- Pathoma states
this is more common in HUS)
o Neurological symptoms (thrombi in vessels of the CNS- Pathoma states
this is more common in TTP)


-
Lab Values (Pathoma):
o Decreased platelet count
o Increased bleeding time
o Normal PT/PTT (coagulation cascade not affected)
o Anemia with schistocyytes
o Increased megakaryocytes on BM biopsy
 Treatment:
o Plasmapheresis with FFP (removes large vWF multimers)

Note that Pathoma says plasmapheresis removes autoAbs from
circulation (if that is the cause of deficiency); corticosteroids
could also be used in this case to decreased autoAb production
Hemolytic Uremic Syndrome (HUS):
 Presentation: similar to TTP, with damage limited to the kidneys
o Usually seen in CHILDREN*
 Cause: associated with E. coli O157-Hy7
o Verotoxin damages endothelial cells resulting in platelet microthrombi
 Characteristics: same as TTP, but neurological symptoms usually not seen
o Also have increased splenic pooling (90% of platelets sequestered in the
spleen)  splenomegaly
o Lifespan of the platelet is normal, and therefore the patients usually
don’t have bleeding issues
 Lab Findings: same as TTP
 Treatment:
o Platelet transfusion is CONTRAINDICATED (more platelets would be
consumed)
o May require dialysis
Decreased Platelet Function (QUALITATIVE):
o Hereditary:

Glanzmann’s Thrombasthenia:
 Inheritance: autosomal recessive
 Deficiency: GPIIb/IIIa
 Result: impaired platelet aggregation (platelet cannot bind to fibrinogen)
 Diagnosis: platelet aggregation study
o Abnormal aggregation with ADP, EPI, collagen, TXA2
o Normal aggregation with ristocetin

Bernard-Soulier Syndrome:
 Inheritance: autosomal recessive
 Deficiency: GPIb
 Result: impaired platelet adhesion (platelet cannot bind vWF defective
adherence to subendothelial collagen)
 Characteristics:
o Thrombocytopenia (decreased life span of platelet)
o Anemia
o ENLARGED PLATELETS (more immature platelets being released to
compensate for thrombocytopenia)
 Diagnosis: platelet aggregation study
o Normal aggregation with ADP, EPI, collage, TXA2
o Abnormal aggregation with ristocetin

Storage Pool Disorder (SPD):
 Grey Platelet Syndrome:
o Rare autosomal recessive disorder resulting in the absence of ALPHA
granules in the platelet
o Platelets are large
o Patient may or may not have thrombocytopenia
o Platelet aggregation studies abnormal with ADP/EPI/collagen/TXA2, but
normal with ristocetin


Delta Storage Pool Disorders: disorders characterized by the absence/decrease in
the amount of DENSE granules in the platelet
o Hermansky-Pudlak Sydrome: severe oculocutaneous albinism

Patients have NO dense granules

Autosomal recessive
o Chediak-Higashi Syndrome: partial albinism

Large cytoplasmic granules cause defective WBC function

Due to defective microtubule polymerization

Autosomal recessive
o Thrombocytopenia with Absent Radii
o Wiskott-Aldrich Syndrome:

X-linked recessive

Patients present with:
 Eczema
 Thrombocytopenia
 Immune deficiency

Other Platelet Disorders:
 May-Hegglin Anomaly:
o Autosomal dominant
o Giant platelets and thrombocytopenia
o WBCs containing Dohle bodies
o Acquired:

Antiplatelet Drugs:
 ASA: most common cause of defective platelet function
o Single dose defect lasts 7-10 days (entire life of the platelet due to
irreversible inhibition of COX)

Hyperglobulinemia:
 Plasma cell myeloma
 Waldenstrom’s macroglobulinemia

Myeproliferative Disorders

Myelodysplastic Disorders

Uremia: build up of nitrogenous waste due to impaired renal function
 Affects both platelet aggregation and adhesion
Defective Coagulation:
Hereditary Coagulation Disorders:
o Hemophilia A (FVIII):

Inheritance: X-linked recessive

Deficiency: absent or low levels of plasma factor VIII

Presentation:
 Infants develop profuse hemorrhage, joint/soft tissue bleeds and excessive bruising
when they start to become active
o Recurrent, painful hemarthroses (joint bleeds)  joint deformity
 Operative/traumatic hemorrhage may be life threatening

Lab Findings:
 Abnormal (increased) PTT
 Abnormal factor VIII clotting assay
 Normal PT and bleeding time

Prenatal Diagnosis:
 DNA analysis from CVS at 8-10 weeks gestation
 Demonstration of low factor VIII in fetal blood (from umbilical vein) at 16-20 weeks
gestation

Treatment:
 Bleeding episodes treated with factor VIII replacement therapy
o Plasma derived (virally inactivated for patients with HIV/HepC)
o Recombinant (for all children and previously untreated patients)
 Spontaneous bleeding is controlled if patient’s factor VIII level is raised > 5% of
normal
o Maintaining FVIII levels often requires daily treatment (COSTLY)
o
-
Factor levels should be raised to 100% of normal for major surgery (and
maintained at 50% of normal when acute bleeding has stopped)
 Antifibinolytic agents may be added to control mucosal bleeding

Complications of Treatment:
 Serious complication of hemophilia is the development of Abs to INFUSED factor
VIII (occurs in 5-10% of patients)
o Patient refractory to further replacement therapy (VERY HIGH doses have
to be given to achieve significant rise in plasma factor VIII activity)
o Immunosuppression has been used in an attempt to reduced formation
of the Ab
o Hemophilia B (FIX)- Christmas Disease:

Inheritance: X-linked recessive

Deficiency: absent or low levels of plasma factor IX

Presentation: same as hemophilia A
 Can only be distinguished by specific coagulation factor assays

Incidence: less common than hemophilia A (1/5 incidence of A)

Treatment: recombinant factor IX is available
 Note: the half life of factor IX is longer and therefore treatments do not have to be
given as often
o Von Willebrand Disease: most commonly inherited bleeding disorder*

Inheritance: various subtypes (3 important ones have been described), usually with
autosomal dominant inheritance
 Exceptions: types 2N and 3 are autosomal recessive

Deficiency: reduced OR abnormal function of vWF due to point mutation or major deletion
 Quantitative and/or qualitative defects based on subtype of disease

Normal vWF:
 Synthesis: in large multimers
 Function:
o Promotes platelet adhesion to damaged endothelium
o Carries factor VIII

Presentation:
 Mucous membrane bleeding
 Excessive blood loss from superficial cuts and abrasions
 Hemarthrosis and hematomas (joint and subcutaneous bleeds) are RARE*

Laboratory Findings:
 Prolonged bleeding time
 Prolonged PTT (low factor VIII levels due to decreased half-life; vWF normally
stabilizes it)
 Normal PT
 Low vWF quantification test
 Defective platelet aggregation with ristocetin (normal with ADP/EPI/collagen)

Diagnosis:
 May be masked by elevated levels of vWF in acute phase reactions (vWF is an acute
phase reactant)
o Examples: pregnancy, strenuous exercise, stress

Determination of Type:
 Measurement of vWF with multimer analysis
o Type 1: reduction in all types of monomers
o Type 2A: absent large and intermediate multimers
o Type 2B: absent large monomers
o Type 3: absence of all types of monomers

Treatment:
 DDAVP (Desmopressin): for type 1 VWD (reduction in monomers)
o Increases release of vWF from Weibel-Palade bodies
 Factor VIII Concentrates w/vWF: may be given for low levels
Acquired Coagulation Disorders:
o Vitamin K Deficiency:

Source: fat soluble vitamin obtained from green vegetables and bacteria in the gut

o
o
o
o
Deficiency:
 Newborns (sterile gut)
 Later in life (inadequate diet, malabsorption, long-term Abx use, inhibition of
vitamin K with warfarin)
Liver Disease:

Biliary Obstruction: impaired absorption of vitK  decreased FII, VII, IX, X synthesis

Severe Hepatocellular Disease: decreased II, VII, IX, X, V and fibrinogen levels

Decreased Thrombopoietin Production: contributes to thrombocytopenia

Hypersplenism: due to portal HTN  thrombocytopenia
Disseminated Intravascular Coagulation:

Pathologic activation of the coagulation cascade:
 Widespread intravascular deposition of fibrin (microthrombi)
 Consumption of coagulation factors and platelets

Mechanism: consequence of many diseases in which there is a release of procoagulant
material into the circulation
 Causes widespread endothelial damage or platelet aggregation

Examples of Causes (Pathoma):
 Obstetric complications (tissue thromboplastin in amniotic fluid activates
coagulation)
 Sepsis (endotoxins and cytokines cause endothelial cells to make tissue factor)
 Adenocarcinoma (mucin activates coagulation)
 APL (primary granules activate coagulation)
 Rattlesnake bite (venom activates coagulation)

Clinical Manifestations: bleeding AND/OR thrombosis
 Bleeding from venipuncture sites or recent wounds
 Generalized bleeding (GI tract, oropharynx, lungs, UG tract)
 Microthrombi skin lesions, renal failure, or gangrene of extremities (less
common)

Lab Findings:
 Increased PT, PTT and TT
 Decreased fibrinogen
 Decreased platelet count
 Increased fibrinogen split products and D-dimers
o D-dimers best screening test (Pathoma)
 Microangiopathic hemolytic anemia (due to microthombi)
o Schistoscytes on peripheral blood smear

Treatment:
 TREAT UNDERLYING CAUSE** (most important)
 Supportive care includes:
o FFP and platelet concentrates (for severe bleeding)
o Cryoprecipitate (concentrated source of fibrinogen)
o Red cell transfusion (may be required)
o ATIII and protein C concentrates (inhibit DIC)
 Do NOT give:
o Heparin or anti-platelet drugs (may aggravate bleeding)
o Fibrinolytic inhibitors (failure to lyse thombi adverse effects)
Coagulation Factor Inhibitor (Pathoma)*:

Basics: acquired Ab against a coagulation factor that results in impaired factor function
 Most Common: anti-FVIII (would be clinically similar to hemophilia A)

Diagnosis:
 Mixing Study: PTT will not correct upon mixing normal plasma with patient’s
plasma (would correct in simply a factor deficiency)
Disorders of Fibrinolysis (Pathoma)*:

Basics: due to plasmin overactivity leading to excessive cleavage of serum fibrinogen

Examples of Causes:
 Radical prostatectomy  releases urokinase, which activates plasmin
 Liver cirrhosis reduces production of alpha2-antiplasmin,which normally
inactivates plasmin



Presentation: clinically similar to DIC (increased bleeding; no microthrombi*)
 Differences from DIC:
o Normal platelet count
o No D-dimers
Laboratory Findings:
 Increased PT and PTT (plasmin destroys coagulation factors)
 Increase bleeding time (plasmin blocks platelet aggregation)
 Normal platelet count
 Increased fibrinogen split products (serum fibrinogen is lysed)
o NO D-dimers due to absence of fibrin thrombi (ie. the coagulation
cascade has not reached completion)
Treatment: aminocaproic acid (blocks activation of plasminogen)
THROMBOSIS:

Basics:
Hereditary Disorders with Increased Risk of Thrombosis:
o Prevalence of these disorders is as high as bleeding disorders
o Should be suspected in young adults who suffer from:

Spontaneous thrombosis

Recurrent DVT

Thrombosis at an unusual site
Risk Factors for Thrombosis (Acquired):
o Venous stasis and immobility
o Malignancy
o Blood disorders (hyperviscosity, thrombocytosis, PV, ET)
o Estrogen therapy (have increased levels of FII, VII, VIII, IX, X; have decreased ATIII levels)
o Heparin Induced Thrombocytopenia (HIT)

Ab to PF4/heparin complex results in platelet activation/consumption microthrombi

Hereditary Disorders:
Factor V Leiden Gene Mutation: most common inherited cause of increased risk of thrombosis*
o Basics: activated protein C resistance (normally breaks down activated FV)
o Defect: genetic polymorphism (NOT A MUTATION) in the factor V gene (argglu at 506)

Makes factor V less susceptible to cleavage by protein C

Heterozygotes ~5x increased risk of venous thrombosis

Homozygotes ~50x increased risk of venous thrombosis
Anti-Thrombin III Deficiency:
o Inheritance: autosomal dominant

May also be seen in patients with nephritis, due to excessive proteinuria (acquired form)
o Defect:

Decreased synthesis of ATIII (type 1)

Dysfunctional activity of ATIII (type 2)
o Presentation:

Recurrent venous thrombosis starting early in life

Arterial thrombosis occasionally seen

Heparin ineffective (PTT does not rise with standard heparin dosing)
Protein C Deficiency:
o Inheritance: autosomal dominant (with variable penentrance)

Acquired forms are also possible:
 Liver disease (made in the liver)
 DIC
 Sepsis
 Vitamin K deficiency (I added this- assumption since it is vit K dependent)
o Warfarin CONTRAINDICATED: due to development of skin necrosis (vessel occlusion due to formation
of microthrombi)

Protein C has a shorter half life than other coagulation factors (depleted first, resulting in
initially hypercoaguable state during treatment; pre-existing deficiency makes this really bad)
Protein S Deficiency:
o Inheritance: autosomal dominant
o Presentation: similar to protein C deficiency (cofactor for protein C)
Prothrombin G20210:
o Defect: base pair substitution at prothrombin allele G20210A on cs 11 that leads to INCREASED plasma
prothrombin levels (synthesized in the liver)

Prothrombin gets converted to thrombin  increased thrombotic risk (~2x)
o Diagnosis: mutation detected by PCR
Hyperhomocystinemia (may also be acquired):
o Defect: mutation in MTHFR gene (product responsible for generating 5-methylTHF)

5-methylTHF is a cosubstrate for homocysteine conversion to methionine

Results in increased levels of homocysteine (cannot convert to methionine)  increased risk
of both venous and arterial thrombosis
o Another Defect (Pathoma):

Cystathionine beta synthase (CBS) deficiency (normally converts homocysteine to
cystathionine)
Acquired Conditions:
Hyperhomocystinemia (may also be hereditary):
o Vitamin B12 or folate deficiency
Acquired forms of ATIII deficiency: already discussed
Acquire forms of Protein C deficiency: already discussed
Antiphospholipid Syndrome (APS):
o Definition: occurrence of thrombosis OR recurrent miscarriage in association with laboratory evidence
of PERSISTENT antiphospholipid Ab

Example: lupus anticoagulant antibody
o Mixing Study: prolonged PTT that does not correct (coagulation factor inhibitor)
o Antiphospholipid Antibodies: associated with arterial and venous thrombosis

Childhood Conditions Associated with Anti-Phospholipid Antibodies:
 Autoimmune diseases (APS, SLE, juvenile arthritis)
 Pediatric stroke
 Hematological diseases (AIHA)
 Various infections (adenovirus, varicella)

May also see in NORMAL Children: ~5-10% of cases
-
