1. ACQUIRED COAGULATION ABNORMALITIES

2. ACQUIRED COAGULATION ABNORMALITIES - causes
1. Vitamin K deficiency
2. Liver disease
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)

3. 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

4. Vitamin K deficiency-etiology
I. Inadequate supply:
1. Dietary deficiency (leafy green vegetables mcg)
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)

5. 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

6. 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)

7. Treatment Vitamin K doses 10mg FFP (invasive procedure)
Prothrombin complex concentrates
Platelet transfusion
Antifibrynolytic agents (dental extraction)

8. Circulating anticoagulants
Clotting factor inhibitors are
autoantibodies (usually IgG) or alloantibodies (in hemophilia A)
that inactivate coagulation factors
- Laboratory test: prolonged aPTT

9. 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)

10. 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

11. Disseminated intravascular coagulation
DIC
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

12. Clinical conditions that may be complicated by DIC
Severe alergic/toxic reaction
Obstetrical conditions
Amniotic fluid embolism
Abruptio placentae
HELLP syndrome
Solid tumors
Sepsis/severe infection
Trauma
Malignancy
Acute leukemias
Kasabach-Merritt syndrome
Vascular abnormalities

13. ACUTE DIC-CLINICAL PRESENTATION
symptoms of underlying disease
symptom of local thrombosis
hemorrhagic diathesis
shock

14. Diffuse intravascular coagulation Microthrombosis secondary fibrinolysis ↓ platelets FDP clotting factors Ischemic tissue damage Microangiopathic Bleeding anemia tendency

15. 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)

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Plasminogen intrinsic extrinsic exogenous activation activation activation factor XIa, XIIa, kallikrein tPA, uPA streptokinase kininogen or APSAC Plasmin Fibrinogen Fibrin FDP FDP + D-Dimer

23. 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

24. Diferentiation of aquired coagulation abnormalities
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

25. 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)
Heparin treatment
unfractioned heparin or low-molecular weight heparin
acrocyanoza, purpura fulminans, dermal necrosis, venous thromboembolism

26. Treatment – thrombosis predominantes
Continous infusion of UFH
Prophilactic doses of heparin or LMWH
Especially, severe purpura fulminans,
acral ischemia, vascular skin infarction

27. 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

28. CASE PRESENTATION