ACQUIRED COAGULATION ABNORMALITIES

ACQUIRED COAGULATIO

N ABNORMALITIES - causes

1. Vitamin K deficiency

2. Liver disease

3.Clotting factor inhibitors:

circulating anticoagulants

complications of anticoagulant therapy

4. Incraesed consumption or loss of the clotting factors:

a) disseminated intravascular coagulation ( DIC)

b) fibrinogenolysis (primary fibrinolysis)

Coagulation abnormalities of vitamin K deficiency

• vitamin K is essential for the final postribosomal

carboxylation of F II, VII, IX, X and the physiologic

anticoagulants, protein C and protein S

Laboratory features:

• PT (prothrombin time) and F II, VII,

IX, X

• aPTT (activated partial thromboplastin time) may be

prolonged in severe, protracted vitamin K deficiency

• Levels of PIVKA-II (Proteins induced in vitamin K absence) are

more sensitive than PT

Vitamin K deficiency-etiologyI. Inadequate supply:

1. Dietary deficiency (leafy green vegetables 90-120mcg)

2. Destroying the gut flora by administration of broad-

spectrum antibiotics

II. Impaired absorption of vitamin K:

1. Biliary obstruction (gallstone, strictures, tumor)

2. Malabsorption of vitamin K(sprue, celiac disease,

ulcerative colitis)

3. Drugs (cholestyramine)

III. Pharmacologic antagonists of vitamin K (coumarins,

warfarin)

Abnormalities of hemostasis and coagulation in liver diseases (1)

I. Decreased synthesis of coagulation factors

1. Fibrinogen, protrombin, clotting F V, VII, IX, X, XI, XII,

XIII, prekallikrein, high molecular weight kininogen

2. Antiplasmins, antithrombin, protein C and protein S

II. Aberrant biosynthesis

1. Of abnormal fibrinogenu

2. Of abnormal analogues of prothrombin, F VII, IX, X

Abnormalities of hemostasis and

coagulation in liver diseases (2)

III. Deficient clearance

1. Of fibrin monomers, fibrinogen degradation products (FDP)

2. Of activated coagulation factors (IXa, Xa, Xia)

3. Of plasminogen acivators

IV. Accelerated destruction of coagulation factors

1. Intravascular coagulation

2. Localized coagulation (hepatic cell necrosis)

3. Abnormal fibrinolysis

V. Thrombocytopenia and platelet dysfunction (splenomegaly)

Treatment

• Vitamin K doses 10mg

• FFP (invasive procedure)

• Prothrombin complex concentrates

• Platelet transfusion

• Antifibrynolytic agents (dental extraction)

Circulating anticoagulants

Clotting factor inhibitors are

autoantibodies (usually IgG) or

alloantibodies (in hemophilia A)

that inactivate coagulation factors

- Laboratory test: prolonged aPTT

Circulating anticoagulants

I. Antibodies to factor VIII (prolonged aPTT, normal INR)

1. In hemophilia A

2. Postpartum -several months after parturition in asociation with a first

pregnancy

3. Various immunologic disorders (rheumatoid arthritis, SLE, penicillin

allergy)

4. Older patients without underlying disease

II. Other spontaneous inhibitors (rarely)- against factors: V, IX, XIII,

fibrinogen,

III. Lupus anticoagulant (in 30% SLE, rheumatoid arthritis, HIV infection, in

lymphoproliferative disorders, after drugs hydralazine, quinidine,

penicillin)

Acquired hemophilia A

• Common bleeding sites are

soft tissue, skin, and mucous membrane

• Treatment – Factor VIII bypassing agents:- Recombinant activated factor VII- Plasma-derived factor eight-inhibitor bypassing agent (FEIBA, also called activated prothrombine complex

concentrate)

- To eradicate the inhibitor is recommended

Disseminated intravascular coagulation • is an acquired syndrome characterized by

systemic intravascular activation of coagulation,

leading to fibrin deposition in the microvasculature

and small-vessels, contributing to organ dysfunction

• consumption of platelets and coagulation factors

lead to thrombocytopenia and impaired coagulation

and may result in bleeding complications

DIC

Clinical conditions that may be complicated by DIC

• Sepsis/severe infection

• Trauma

• Malignancy

• Acute leukemias

• Kasabach-Merritt syndrome

• Vascular abnormalities

• Severe alergic/toxic reaction

• Obstetrical conditions

• Amniotic fluid embolism

• Abruptio placentae

• HELLP syndrome

• Solid tumors

ACUTE DIC-CLINICAL PRESENTATION

• symptoms of underlying

disease

• symptom of local thrombosis

• hemorrhagic diathesis

• shock

Diffuse intravascular coagulation

Microthrombosis secondary fibrinolysis ↓ platelets FDP clotting factors

Ischemic tissue damage Microangiopathic Bleeding anemia tendency

Acute DIC - laboratory features: Increased D-Dimer level

FDP level

AT level

platelet level

• Bload smear - schistocytes

fibrinogen level

TT (Thrombin time)

aPTT

PT (Prothrombin time)

Acute DIC diagnosis

• The basis of the diagnosis is the knowledge of

the underlying diseases

• Patients suffering from acute DIC need urgent

therapy

• DIC should always be taken into consideration

if a complex coagulation defect in combination

with a underlying disease is observed

Diagnostic algorithm for

the diagnosis of overt DIC

(1)• Risk assessment:

• Does the patient have an underlying

disorder known to be associated

with overt DIC?

• If yes, proceed

Diagnostic algorithm for the diagnosis of overt DIC (2)

- Order global coagulation tests

•Platelet count

(>100=0, <100=1, <50=2)

•Elevated fibrin-related markers

(FDP no increase:0, moderate increase:2, strong increase:3)

•Prolonged PT

(<3sec.= 0, >3 but <6 = 1, >6sec. = 2)

•Fibrinogen level (>1g/L=0, <1g/L=1)

If ≥ 5: compatible with overt DIC

CHRONIC (compensated) DIC

In chronic DIC, the activation of the

hemostatic system is minimal since

negative feedback mechanisms as well as

inhibitors can limit the activation process

so that microthrombi do not occur and

bleeding episodes are rare phenomena

Chronic DIC - etiology

1. Obstetric complications: eclampsia, the death fetus syndrom

2. Vascular disorders:

giant hemangiomas (Kasabach Merrit syndrome), Leriche

syndrome, Raynaud,s disease

3. Carcinomas

4. Hematology disorders: myelofibrosis, polycythemia vera, PNH

5. Reumathoid disorders: SLE, sclerodermia

6. Kidneys disorders: glomerulonephritis, HUS

7. Another: vasculitis allergica, diabetes mellitus

PRIMARY FIBRINOLYSIS (FIBRINOGENOLYSIS)

DEFINITION:

primary fibrinolysis occurs when

plasmin is generated in the absence of

DIC

◊ This has been described in hepatic disorders, prostatic carcinomas, and cases without apparent cause

◊ At present, most cases of primary fibrynolysis are iathrogenically induced during thrombolytic therapy

Plasminogen

intrinsic extrinsic exogenous activation activation activationfactor XIa, XIIa, kallikrein tPA, uPA streptokinasekininogen or APSAC

Plasmin

Fibrinogen Fibrin

FDP FDP + D-Dimer

Acquired coagulation abnormalities - diagnostics

I History

II Physical examination

III Laboratory features

- morphology

- blood smear

- bleeding time

- prothrombin time (PT), INR

- aPTT

- thrombin time (TT)

- fibrinogen

- fibrin(ogen) degradation products (FDP)

- D-dimer

- antithrombin

PT aPTT Platelet Fibrinogen TT FDP D-

Dimer AT

count

Acute DIC

Chronic DIC N N N N N

Fibrinogenolysis N N N N

N

Heparin overdosage N N N N

N N

Dicumarol N N N N N

N

overdosage or

prothrombin complex

factors defficiency

Diferentiation of aquired coagulation abnormalities

ACA – DIC THERAPY

1. Treatment of the underlying disorder

2. Treatment of shock

3. Replacement therapy

- platelet concentrates

- RBC

- FFP

- Cryoprecipitate (fibrinogen)

- Activated protein C (drotrecogin alfa)

4. Heparin treatment

unfractioned heparin or low-molecular weight heparin

acrocyanoza, purpura fulminans, dermal necrosis, venous thromboembolism

Treatment – thrombosis predominantes

• Continous infusion of UFH

• Prophilactic doses of heparin or LMWH

• Especially, severe purpura fulminans,

acral ischemia, vascular skin infarction

Treatment - bleedings

• Transfusion of platelets or plasma (components)

including FFP and/or prothrombin complex

concentrate (fluid overload)

• Severe hipofibrynogeneamia (<1g/L):

FFP, fibrionogen concentrate and cryopercipitate

CASE PRESENTATION