Download Disorders of Hemostasis Hereditary Disorders of Hemostasis Von

Disorders of Hemostasis
Hereditary Disorders of Hemostasis
Von Willebrand’s Disease

The most common inherited bleeding disorder in humans (1% to 2 % of the
Population)

Caused by a quantitative or qualitative defect of the vWF

vWF is a protein synthesized by endothelial cells, megakaryocytes, and
platelets that is essential for platelet plug formation.
o vWF binds platelets to subendothelial surface of injured blood vessels.
After binding to the subendothelium, vWF binds the GPIb receptor on
the surface of platelets.
o vWF also participates in platelet aggregation by binding to the
GPIIb/IIIa receptors on the surface of several platelets.
o It is also important in coagulation as a carrier protein and stabilizer
for factor VIII

vWF has several potential binding sites:
o On collagen for adherence to the subendothelium
o On the platelet GPIb receptor for platelet adhesion to collagen
o On the platelet GPII3/IIIa receptor for platelet aggregation
o On factor VIII for its carrier function

Classification of vWD
o Type I (the most common form) - a quantitative deficiency of vWF.
o Type 2 – several subtypes with different qualitative defects vWF
o Type 3 (least common, most severe) – complete absence of vWF

Acquired forms of vWD
o
o
o
o
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Lymphoproliferative diseases
Autoimmune disease
Hypothyroidism
Valvular heart defects
Medications such as valproic acid

Clinical manifestations of vWD
o
o
o
o
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o

Mucocutaneous bleeding
Easy bruising
Epistaxis
Gingival bleeding
GI bleeding
Menorrhagia
History of significant bleeding with previous surgeries
Laboratory diagnosis of vWD
o Platelet count, PT and PTT may well be normal
o Hematology consult and specialized testing may be in order
o Ristocetin cofactor activity - most sensitive and specific test for vWD

Two established modes of treatment for vWD - desmopressin and factor
replacement therapy
o Desmopressin (DDAVP) – a synthetic analog of the antidiuretic
hormone vasopressin

Triggers the release of both vWF and factor VIII

0.3 g/kg for pre-op prophylaxis will increase factor VIII and
vWF two- to five-fold in most patients.

Side effects – flushing, tachycardia, headache from the
vasomotor effects of DDAVP, and hyponatremia and seizures
from the antidiuretic effects. (Monitor serum Na)
o Factor VIII and vWF concentrate replacement therapy

For patients who do not respond to DDAVP

Haemate-P, cryoprecipitate or FFP
o Antifibrinolytic amino acid therapy

Sometimes used in combination with DDAVP to manage vWD
patients during the perioperative period.

Anti-fibrinolytic drugs interfere with the lysis of newly formed
clots

-Aminocaproic acid 50 to 60 mg/kg q 4 to 6 hours

Tranexamic acid 20 to 25 mg/kg q 8 to 12 hours
o Anti-platelet drugs should be avoided in patients with vWD.
Hemophilias

Inherited bleeding disorders caused by deficiencies of certain coagulation
factors
o Hemophilia A – deficiency of factor VIII
o Hemophilia B – deficiency of factor IX
o Hemophilia C – deficiency of factor XI

Both are X-linked recessives and occur almost exclusively in males

Clinical presentation
o Unexplained bruising or bleeding in young males
o Arthropathies due to recurrent hemarthrosis and chronic synovitis
o Hematuria

Testing
o APTT prolonged in both Hemophilia A and B
o PT, platelet count, vWF levels, and fibrinogen levels are normal
o Factor VIII and IX levels are low

Treatment and Perioperative Management
o Factor replacement therapy – either plasma-derived concentrates that
have been treated by viral attenuation, or, more commonly now,
recombinant factor VIII or factor IX
o Obtain hematology consult for perioperative management advice.
o DDAVP will increase plasma factor VIII and vWF concentrations and
may be effective in mild hemophilia A.
o Antifibrinolytics may be useful prior to dental procedures, but are
contraindicated in bleeding episodes involving joints or the urinary
tract because clots that do form may not be lysed for a long period of
time.
Protein C and Protein S Deficiency

Hereditary deficiencies of protein C and protein S

Associated with thromboembolic events originating on the venous side of the
circulation (eg, DVT, PE, and stroke) as a consequence of paradoxical
embolization.

Patients with a history of thromboembolic events and a deficiency of protein
S or protein C should remain on anticoagulants indefinitely.
Inherited platelet disorders

Involve quantitative or qualitative impairment of platelet function

Idiopathic thrombocytopenic purpura (ITP)
o Commonly found in children
o Adult patients present with isolated thrombocytopenia and a normal
peripheral blood smear
o Secondary immune thrombocytopenia can occur following exposure
to drugs, herbs, foods, or other substances
o Can also follow SLE, antiphospholipid syndrome, B-cell malignancies,
and HIV
Acquired Disorders of Hemostasis
Acquired Disorders of Platelets
Thrombocytopenia

Platelets are produced by megakaryocytes in the bone marrow in response to
thrombopoetin, which is synthesized in the liver.

Causes of thrombocytopenia:
o Inadequate production by the bone marrow
 Secondary to bone marrow suppression of any cause
o Increased peripheral consumption or destruction (non-immune
related)
 Extensive activation of coagulation mechanisms after trauma,
burns, and crush injuries, or contact with large vascular grafts
 Extensive vasculitis as occurs with toxemia of pregnancy
 DIC
o Increased peripheral destruction (immune related)
 Drug related, autoimmune reactions, and alloimmunization
o Dilution of circulating platelets
o Sequestration
Uremia

Platelet dysfunction is common in uremia

Accumulated substances interfere with ability of the platelet to expose the
PF3 phospholipid surfaces.

Dialysis improves the hemostatic defect

DDAVP improves platelet adhesiveness

Erythropoiten will gradually improve platelet function

Platelet concentrates may be indicated if life-threatening bleeding occurs in a
uremic patient.
Anti-Platelet Drugs

Numerous medications are administered expressly for the purpose of
platelet inhibition in order to reduce the risk of MI, stroke and other
thromboembolic events. They induce platelet dysfunction by several
mechanisms:
o
o
o
o

Inhibition of cyclooxygenase
Inhibition of phosphodiesterase
ADP receptor antagonism
Blockade of glycoprotein IIb/IIIa receptor
Cyclooxygenase (COX) inhibitors:
o Aspirin – non-selective COX inhibitor

Irreversibly inhibits platelet cyclooxygenase, which blocks the
synthesis of thromboxane A2, a potent platelet aggregator and
vasoconstrictor.
o NSAIDs inhibit cyclooxygenase in a similar manner, but their effect is
reversible in 24 hr with clearance of the drug.
o COX-2 inhibitors selectively inhibit the COX-2 isoform, which
mediates pain and inflammation, and spare the COX-1 isoform,
responsible for gastric damage, decreased renal blood flow, and
platelet thromboxane A2 synthesis.

Phosphodiesterase inhibitors
o Cyclic AMP is an inhibitor of platelet aggregation and cAMP levels are
increased by inhibition of phosphodiesterase.
o Dipyridamole and cilostazol act by this mechanism

ADP receptor antagonists
o Clopidogrel (Plavix) and ticlopidine (Ticlid) block the ADP receptor on
the platelet surface, which suppresses activation of the GPIIb/IIIa
receptor.
o They non-competitively and irreversibly inhibit ADP-induced platelet
aggregation.
o Platelet function normalizes 7 days after discontinuation of
clopidogrel and 14 days after for ticlopidine.

GP IIb/IIIa receptor antagonists
o Abcixamab (ReoPro), a monoclonal antibody, Tirofiban (Aggrastat),
and Eptifibatide (Integrilin).
o Block binding of fibrinogen and vWF factor to platelet GPIIb/IIIa
receptors, inhibiting platelet aggregation.
o Effects are reversible, half-lives are relatively short
o All are associated with thrombocytopenia
Herbal Medications and Vitamins

Several herbal medications, including ginkgo biloba, ginseng, garlic, and
ginger, may inhibit platelet function.

Vitamin E is also a platelet inhibitor
Other Conditions

Myeloproliferative and myelodysplastic syndromes can induce intrinsic
defects in platelets. Platelets may be abnormal in both morphology and
function.
Acquired Disorders of Clotting Factors
Liver Disease
Chronic liver disease is associated with abnormalities of all three phases of
hemostasis: primary hemostasis, coagulation and fibrinolysis.

Impaired primary hemostasis is the result of both thrombocytopenia
(decreased production) and impaired platelet function (insufficient clearance
of FDPs, which coat the surface of platelets and impair aggregation).

Coagulation is impaired because factor production decreases and
consumption increases.

Fibrinolysis is increased as a result of decreased clearance of t-PA from the
circulation by the impaired liver, and decreased hepatic synthesis of alpha 2antiplasmin, a natural inhibitor of plasmin.
DIC

DIC is characterized by excessive deposition of fibrin throughout the vascular
tree, with simultaneous depression of normal coagulation inhibitory
mechanisms and impaired fibrin degradation.

DIC is triggered by the appearance of procoagulant material (eg, tissue
factor) in the circulation in amounts sufficient to overwhelm the mechanisms
that normally restrain and localize clot formation.
o May result from extensive tissue injury – burns or trauma
o May also result from the release of tissue factor into the circulation
 Sepsis is the most common cause.
 Amniotic fluid embolus, fetal death in utero, preeclampsia
 Severe head injury or stroke
 Any cause of systemic inflammatory response
 Hemolytic transfusion reactions

The accelerated process of clot formation causes both tissue ischemia and
critical depletion of platelets and clotting factors.

Simultaneously, the fibrinolytic system is activated and plasmin is generated
to lyse the extensive fibrin clots.

Fibrin degradation products appear in the circulation.
o FDPs stimulate the release of plasminogen activator inhibitor from
endothelium, and thrombolysis becomes impaired.
o FDPs also inhibit platelet aggregation and prevent normal
crosslinking of fibrin monomers.

Depleted of platelets and clotting factors, and inhibited by FDPs, the
coagulation system fails and the patient bleeds.

Simultaneously, microvascular occlusion by fibrin causes tissue ischemia,
contributing to multi-organ failure.

Laboratory diagnosis - increased PT and PTT, thrombocytopenia, decreased
fibrinogen level, and the presence of FDPs and D-dimers

Treatment should focus on management of the underlying condition.
o Correct hypovolemia, acidosis, and hypoxemia.
o Platelet infusion for thrombocytopenia
o FFP to replace deficient clotting factors
o Cryoprecipitate to raise fibrinogen
o Heparin may be useful if thrombosis is a significant problem
Vitamin K Deficiency

Vitamin K is required for the hepatic synthesis of factors II, VII, IX and X, as
well as proteins C and S.

Each of the vitamin K dependent factors undergoes the enzymatic addition of
a carboxyl group. This step requires the presence of vitamin K. The carboxyl
group enables these factors to bind to phospholipid surfaces. Without
vitamin K, factors II, VII, IX and X are produced in normal amounts but are
nonfunctional.

Vitamin K is a fat-soluble vitamin and therefore requires bile salts for
absorption from the jejunum. Patients with biliary obstruction, pancreatic
insufficiency, malabsorption syndromes, GI obstruction, or rapid GI transit
can develop vitamin K deficiency as a result of inadequate absorption.

Vitamin K deficiency will cause prolongation of the PT.

Vitamin K can be administered PO, IM, or IV

Therapy can take several days, but improvement of the coagulation
abnormality should be apparent within 6 to 8 hours after IM or IV
administration.
Warfarin Therapy

Warfarin produces its anticoagulant effect by competing with vitamin K for
carboxylation binding sites in the liver.

Warfarin leads to the depletion of factors II, VII, IX, and X.

At theraputic doses, only the PT and INR will be prolonged.

If time allows, stop the medication 4 to 5 days ahead of surgery to normalize
the PT.

More rapid reversal can be accomplished with oral or parenteral vitamin K.

Immediate reversal is achieved with FFP, prothrombin complex concentrate,
or recombinant factor VIIa. However, vitamin K should still be administered
because of the short half-life of those substances.
Heparin Therapy

Heparin inhibits coagulation principally by binding to antithrombin III, which
greatly increases the inhibitory effect of ATIII on thrombin and other
coagulation factors.

Advantages of unfractionated heparin over LMWH or fondaparinux:
o Immediate onset
o Short half-life of 30 to 60 min
o Reversibility with protamine

Needs to be closely monitored because of unpredictable pharmacokinetics

Generally, the use of low-dose or mini-dose unfractionated heparin for
thromboprophylaxis poses a low risk for hemorrhage during surgery.

On the other hand, patients receiving therapeutic doses of standard heparin
are at high risk of bleeding during surgery.

Heparin should be stopped at least 6 hours before surgery, and restarted
about 12 hours after surgery.

Protamine sulfate can be used for immediate reversal of heparin
anticoagulation.

Complications of heparin therapy:
o Heparin-induced thrombocytopenia/thrombosis (HITT)
 HITT type 1 is self-limiting and requires no treatment.


HITT Type 2 - as many as 5% of patients who receive heparin
therapy for 5 days will develop thrombocytopenia as a result of
antibodies (usually IgG) directed against platelet factor 4heparin complexes on the platelet surface.

The onset on HITT is signaled by a rapid drop in the platelet
count 5 to 10 days after initiation of heparin therapy. Mortality
is 20% to 30%.

Though HITT is most often identified by thrombocytopenia,
not all patients become thrombocytopenic. In these patients,
the onset of HITT may be heralded by thrombotic events
including DVT, PE, limb ischemia, MI, or stroke.

Treatment entails withdrawal of heparin after the institution of
alternate anticoagulation.
Resistance to heparin can occur in patients who are deficient in ATIII either
on a hereditary or acquired basis (the latter is seen with prolonged heparin
therapy or in the presence of a consumptive coagulopathy). Heparin function
can be restored by the administration of ATIII concentrates or FFP.
Low-molecular-weight-heparin (LMWH) Therapy

LMWH is heparin cleaved into shorter fragments. Like heparin, LMWH acts
by enhancing the effect of ATIII.

LMWH has a delayed onset of 20 to 60 minutes, and a longer half-life than
heparin. Peak plasma concentrations occur approximately 4 hr after the
initial dose, and activity persists up to 24 hr.

Used mostly for DVT prophylaxis and treatment

Monitoring is not usually required or performed, but if it is deemed
necessary, anti-Xa level is the appropriate test.

Major disadvantage of LMWH is that it cannot be reversed

LMWH causes less platelet inhibition than standard heparin, and is
associated with a lower incidence of heparin-induced thrombocytopenia.
Direct Thrombin Inhibitors

Includes hirudin, argatroban, lepirudin, and bivalirudin
o Used for anticoagulation during CPB when there are contraindications
to heparin.
o There is no reversal drug. Termination of effect is dependent on renal
excretion.
Inhibitors of Xa

Includes fondaparinux and idraparinux
o Increasingly popular for DVT prophylaxis because of once-a-day
dosing and lack of need for monitoring.
o Also, less risk of osteopenia and heparin-induced thrombocytopenia
o Long half lives, no antidote, renal excretion
o PT, PTT and ACT are not affected
Thrombolytic agents

Classified either as native tissue plasminogen activators (streptokinase,
urokinase) or as exogenous tissue plasminogen activators (alteplase,
tenecteplase)
o Native tissue plasminogen activators are potent activators of
plasminogen to form plasmin
o Exogenous tissue plasminogen activators are more fibrin selective,
with less effect on circulating plasminogen.
o Both function as anticoagulants as well as thrombolytics because
fibrinolysis generates increased amounts of circulating fibrin
degradation products that inhibit platelet aggregation.
o In general, surgery should be delayed for 10 days and until clotting
tests are normal.
Hypercoagulable Disorders

Disorders that predispose patients to thrombosis
o Can be inherited or acquired
o Can be arterial or venous

Acquired hypercoagulable disorders
o Predispose patients to thrombosis by:
 Activating the coagulation system
 Inhibiting the fibrinolytic system
 Initiating platelet activation
o
o
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o
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Smoking
Heparin-induced thrombocytopenia (HITT syndrome)
Antiphospholipid syndrome
Pregnancy
Oral contraceptives
Diabetes Mellitus
Polycythemia
Hyperfibrinogenemia
Malignancy
Sepsis
Trauma
Hyperthermia
Immobility
o Venous thrombosis is associated with venous stasis, hypercoagulable
states, and vascular damage.
o Venous blood flow is impaired in pregnancy, and with abdominal
tumors, varicose veins, or conditions involving vascular damage such
as vasculitis.
o Hypercoagulable states are commonly associated with coronary
artery disease, diabetes, malignancy, nephritic syndrome, prolonged
bed rest, postoperative status, and sepsis.
o Patients with artificial heart valves, atrial fibrillation, and certain
types of valvular heart disease have an increased risk of arterial
thrombosis.

Congenital hypercoagulable disorders lead to intraoperative deep vein
thrombosis and pulmonary embolism:
o Involve congenital abnormalities of procoagulant and anticoagulant
proteins
o Factor V Leiden mutation
o Protein C or S deficiencies
o Anti-thrombin deficiency
o Hyper-homocysteinemia
o Increased Factor VIII or Factor IX levels
o Dysfibrinogenemia
o Increased plasminogen activator inhibitor levels
o Decreased plasminogen activator
o Hereditary conditions should be suspected in patients with a positive
family history, recurrent thrombolic events, or thromboemboli at a
young age without predisposing factors.