Thromboembolic Disorders

Thromboembolic Disorders

The risk of venous thrombosis & pulmonary embolism in otherwise healthy women is considered highest during pregnancy & puerperium.
The risk during the 3rd trimester & the 1st 6 weeks postpartum were six & 22 times higher respectively.

The thromboembolism rate has increased significantely during the past 2 decades, although this increase may reflect the higher sensitivities of newer diagnostic modalities.
Pulmonary embolism still remains a leading cause of maternal death in the united states.

Pathophysiology:

Stasis, local trauma to the vessel wall & hypercoagulability predispose to venous thrombosis.The risk of each of these inceases during normal pregnancy.
For ex. Compression of the pelvic veins & inferior vena cava by the enlarging uterus renders the lower extremity venous system vulnerable to stasis.

Risk factors:

Obstetrical:
1.cesarean delivery
2.diabetes
3.hemorrhage & anemia
4.hyperemesis
5.immobility-prolonged bed rest
6.multifetal gestation
7.multiparity
8.preeclampsia
9.puerperal infectio


General:
1.35 yrs or older
2.cancer
3. connective tissue disease
4.dehydration
5.infection & inflamatory disease
6.myeloproliferative disease
7.nephrotic syndrome
8.obesity
9.oral contaceptive use

10.orthopedic surgery

11.paraplegia
12.prior thromboembolism
13.sickle cell disease
14.smoking
15.thrombophilia
The most important of these is a personal history of of thrombosis.

Thrombophilias:

Several important regulatory protiens act as inhibitors in the coagulation cascade.
Inherited or acquired deficiencies of these inhibitory protiens are collectively referred to as thrombophilias.
These can lead to hypercoagulability & recurrent venous TE.


Inherited thrombophilias:
Patients often have a family history of thrombosis.They are found in up to half of patients present with TE before age 45 particularly in the absence of well recognized risk factors , such as surgery or immobilization.

Antithrombin deficiency

Protien C deficiency
Protien S deficiency
Activated protien C resistance-Factor 5 Leiden Mutation
Prothrombin G20210A Mutation
Hyperhomocysteinemia
Other Thrombophilia Mutations

Acquired Thrombophilias:

APS
Heparin induced thrombocytopenia
cancer

Antiphospholipid Antibodies:

These autoantibodies are directed against cardiolipins or against phospholipid –binding protiens such as B2-glycoprotien.
They are commonly found in patients with SLE.

Women with moderate to high levels of these antibodies may have antiphospholipid syndrome,which is defined by a number of clinical features:
In addition to vascular thrombosis, these include:
1.At least one unexplained fetal death at or beyond 10 weeks


2.at least one preterm birth before 34 weeks because of eclampsia,sever preeclampsia,or placental insufficiency.
3.at least three unexplained consecutive spontaneous abortions before 10 weeks.
In these women,TH-either venous or arterial- most commonly involves the lower extemities.

Deep vein thrombosis:

During pregnancy,most venous thrombosis are confined to the deep veins of the lower extremity.
Approx. 70% of cases are located in the iliofemoral veins without involvement of the calf veins.

Most cases during pregnancy are left sided, hypothesizes that this results from compression of the left iliac vein by the right iliac & ovarian artery,both of which cross the vein only on the left side.

Classic thrombosis involving the lower extremity is abrupt in onset, & there is pain & odema of the leg & thigh.
occasionally, reflex arterial spasm causes a pale,cool extremity with diminshed pulsations
Conversely,there may be appreciable clot , little pain, heat or swelling.

Between 30 to 60 percent of women with a confirmed lower extremity acute deep vein thrombosis have an asymptomatic pulmonary embolism.

Diagnosis:

1.clinical Dx., is confirmed in only 10%.
2.US , this noninvasive technique is the most used 1st line test .
3. MRI
4. D-Dimer screening tests
5.Venography


Management:
Anticoagulation is initiated with either unfractionated or low molecular weight heparin.
Most recommend LMWH during pregnancy because of better bioavailability,longer plasma half life,more predictable dose response, reduced risks of osteoporosis & thrombocytopenia & less frequent dosing.

During pregnancy , heparin therapy is continued, & for postpartum women anticoagulation is begun simultaneously with warfarin.
After symptoms have abated,graded ambulation should be started.
Elastic stocking are fitted, & anticoagulation continued.

Recovary to this stage usually takes 7 to 10 days.

Graduated compression stocking should be continued for 2 years to reduce the incidence of postthrombotic syndrome.
This syndrome can include chronic leg paresthesia or pain, intractable edema, skin changes & leg ulcers.

Unfractionated heparin:

Used for initial Rx.of TE & in cases in which delivery & surgery may be necessary.
UFH can be given by one of two alternatives:
1.initial i.v. therapy followed by s.c. UFH given every 12 hours. Or
2.twice daily, adjusted dose s.c. UFH with doses adjusted to prolong the (aPTT) into the therapeutic range 6 hrs postinjection.

The therapeutic dose for s.c. UFH is usually 10,000 units or more every 12 hours.

For i.v. therapy, UFH is initiated with a bolus dose of 70 to 100 U/kg , about 5000 to 10,000 U followed by continous i.v. infusions beginning at 1000 U/hr or 15 to 20 U/kg/hr,
Titrated to achieve an aPTT of 1.5 to 2.5 times control values.


i.v. Rx. Should be continued for at least 5 to 7 days after which Rx. Is converted to s.c. heparin.
The duration of full anticoagulation is recommended throughout pregnancy & postpartum for a minimum of 3 months.

LMWH:

This is a family of derivatives of UFH & their molecular weights average 4000 to 5000 daltons compared with 12000 to 16000 daltons for conventional heparin.
None of these heparins cross the placenta & all exert their anticoagulant activity by activating antithrombin.

The primary difference is their relative inhibitory activity against factor Xa & thrombin.
UFH has equivalent activity against factor Xa & thrombin , but LMWH have greater activity against factor Xa than thrombin

They also have more anticoagulant response & fewer bleeding complications than UFH because of their bioavailability , longer half-life , dose independent clearance & decraesed interference with platelets.

LMWH available for use in pregnancy include enoxaparin ,tinzaparin ,& dalteparin.

Enoxaparin the dose is 1mg/kg twice daily , Rx. Monitored by peak anti-factor Xa activity 3 hours post injection with a target therapeutic range of 0.4-1.0 U/ml.

Labor & delivery:

Women receiving LMWH should be converted to the shorter half life UFH in the last month of pregnancy.
Heparin should be stopped 24 hrs before labor induction or casarean.
Reversal of heparin with protamin sulfate is rarely required & not indicated with prophylactic doses.
Heparin is restarted 4 to 6 hrs after vaginal delivery & 6 to 12 hrs after CS.


Warfarin:
venous thrombosis is usually treated with i.v. heparin & oral warfarin .
The initial dose of warfarin is 5 to 10 mg for the 1st two days.
Subsequent doses are titrated to achieve an INR of 2 to 3 .

Safety in pregnancy:

UFH & LMWH are safe during pregnancy & lactation (they don’t cross the placenta).
Warfarin is contraindicated because it cross the placenta & may cause fetal death & malformations.
However it is safe during breast feeding.

Complications of anticoagulation:

1.hemorrhage
2.thrombocytopenia
3.osteoporosis
The later two are unique to heparin & may be reduced with LMWH.

Superficial venous thrombophlebitis:

Thombosis limited to the superficial veins of the saphenous system , it is typically seen with varicosities & treated with analgesia, elastic support , heat , & rest.

Pulmonary embolism:

It causes 10% of maternal deaths .
There is equal prevalence for AP & PP embolism with higher mortality rate for the PP.
70% with PE have associated clinical evidence of DVT.
30 to 60% of women with DVT have a silent PE.


Clinical presentation:
Dyspnea,chest pain , cough ,syncope , hemoptysis , tachypnea & tachycardia.
Right axis deviation & T-wave inversion in the anterior chest leads may be evident on ECG.

Dx.:

It requires a high index of suspicion
1.CT pulmonary angiography
2.MR angiography
3.Intravascular pulmonary angiography
4. Ventilation-perfusion lung scan

Management:

Immediate Rx. Is full anticoagulation similar to that for DVT.
A number of complementary procedures may be indicated:
1.Vena caval filters
2.Thrombolysis using thrombolytic agents
3.Embolectomy by surgery

Consumptive coagulopathy:

Obstetrical syndrome also termed DIC.
It is secondary to many conditions:
1.placental abruption
2.AF embolism
3.dead macerated fetus
4.sepsis
5.preelampsia & HELLP
6.obstetrical hemorrhage
7.acute fatty liver disease of pregnancy
8.diminished hepatic synthesis of procoagulants


Normal coagulation & fibrinolysis can be activated via two pathways:
The extrinsic pathway is active by thromboplastin from tissue destruction .
The intrinsic pathway is initiated by collagen & other tissue components that become exposed with loss of endothelial integrity.

The pathologically activated cycle of coagulation & fibrinolysis becomes clinically important when coagulation factors & platelets are sufficiently depleted to cause bleeding – hence consumptive coagulopathy.

Several obstetrical conditions are accompanied by release of potent inciting factors for clinically significant CC.
The best known & most common ,& therefore most serious,results from thromboplastin release with abruption.
Also profound coagulation factor depletion following entry of AF into maternal circulation.
Also release of endotoxins from gram –ve & exotoxins from gram +ve bacteria.

Dx.:

DIC score:
1.presence of known underlying disorder ass. With DIC:no=0 ; yes=2
2.coagulation tests: platelets:>100=0; <100=1 ; <50=2
D-dimer levels increased: no=0; moderate=2; strong=3

PT prolongation(sec): <3=0; >3 but<6=1 ; >6=2

Fibrinogen(mg/dl): >100mg/dl=0 ; <100mg/dl=1
Total score:
Equal & more than 5:compatible with overt DIC
Less than 5:suggestive of nonovert DIC


In late pregnancy, plasma fibrinogen levels increase to 300 -600 mg/dl.Even with sever consumptive coagulopathy, levels may be high enough to protect against hypofirinogenemia.
Fibrinolysis cleaves fibrin & fibrinogen into various fibrin degradation products that are detected by several sensitive test systems.

Blood products commonly transfused:

1.whole blood :about 500ml;Hct 40% , contains RBCs,plasma,600-700mg fibrinogen , no platelets.Restores bld volume & fibrinogen,increases Htc 3-4 % per unit.
2.packed RBCs:250-300ml;Hct 55-80% ,RBCs minimal, no fibrinogen , no platelets.Increases Hct 3-4% per unit.

3.FFP:250ml;600-700mg fibrinogen ,no platelets.Restores circulating volume & fibrinogen.
4.Cryoprecipitate:15ml,frozen,200mg fibrinogen ,other clotting factors, no platelets.
15-20 units or about 3-4g will increase baseline fibrinogen 150mg/dl.

5.Platelets:50 ml,one unit raises platelet count about 5000/ML,6-10 units transfused .

Single donar bag preferable.

Mx.:

1.indentification & removal of the source of coagulopathy
2.rapid replacement of procoagulants is indicated
3.vigorous restoration & maintenance of the circulation to treat hypovolemia cannot be overemphasized.

4.with adequate perfusion, activated coagulation factors,fibrin & fibrin degradation products are removed by the RES along with restoration of hepatic & endothelial synthesis of procoagulants.



Dilutional coagulopathy:
A major drawback of Rx. For massive hemorrhage with crystalloid solutions & packed RBCs is depletion of platelets & clotting factors.This leads to dilu.coag. , indistinguishable from DIC.
Fotunately, Rx. For both is similar.

Thrombocytopenia is the most frequent coagulation defect with blood loss & multiple transfusions.
Also there may be hypofibrinogenemia & prolongation of the PT & PTT.

So, when red cell replacement exceeds five units , check platelets count,clotting studies ,& plasma fibrinogen.
The platelet count should be maintained above 50,000 .
Fibrinogen level < 100mg/dl or prolonged PT & PTT is indication for replacement.
FFP given in doses of 10-15 ml/kg or alternatively cryoprecipitate is infused.