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Keywords:
Peripartum Cardiomyopathy
Heart failure
Thrombophilic disorder






















Manuscript

Peripartum cardiomyopathy (PPCM) is a rare condition of late pregnancy or early puerperium characterized by severe left ventricular systolic dysfunction and symptoms of heart failure.
It can favourably evolve in rapid recovery. However many factors, including left ventricular thrombosis, might concur in its poor outcome requiring a use of nonpharmacologic treatment (ultrafiltration, mechanical support, heart transplantation). 
The increase of Fibrinogen and Factor VIII levels is an important risk factor for thrombotic events in pregnancy and puerperium. Furthermore, severe ventricular dysfunction can per se promote the development of thrombi, due to blood stasis. When vascular thrombosis occurs, coagulative C protein and acquired Antithrombin (AT) deficiencies are associated. 
We present a complicated case of a young woman affected by PPCM associated with intracardiac and venous thrombosis caused by a thrombophilic disorder. The patient, refractory to medical treatment, intra-aortic balloon pump (IABP) counterpulsation and mechanical ventilator support, underwent urgent heart transplantation.

Case Report

A 27-year-old woman (height 167cm, weight 60kg), developed progressive dyspnoea two months after delivering a healthy baby boy.
She was admitted to the Intensive Cardiology Unit of a University Hospital with diagnosis of acute heart failure.
Transthoracic Echocardiogram (TTE) and Cardiac Magnetic Resonance Imaging (MRI) showed severe left and right ventricular dysfunction  (LVEF 25%), and left ventricular apical thrombus. 
The patient was initially treated with diuretics, vasodilators and oral anticoagulant therapy overlapping low molecular weight heparin (LMWH) until a therapeutic INR was achieved. 
After one month, she also presented with hepatic dysfunction secondary to cardiac failure, which requires interruption of oral anticoagulation therapy.
Due to clinical deterioration, the patient was transferred to our Cardiovascular Intensive Care Unit for a cardiac transplant evaluation.
Upon admission, she presented unstable hemodynamic parameters (Arterial Pressure 80/50 mmHg, Heart Rate 115 beats/minute), lactate acidosis (4.5 mmol/l) and slight dyspnoea.
Laboratory data evidenced severe AT deficiency (26%) and coagulative C protein deficiency (37%), high Factor VIII (>200%) and D Dimer (3.618 ng/ml), and normal Fibrinogen values (390 mg/dl). Thrombophilia screening showed heterozygotes phenotype for Methylenetetrahydrofolate Reductase (MTHFR) with normal homocysteinemia (6.3 microm/l). The patient�s group blood was A. Testing for Heparin Induced Thrombocytopenia (HIT) was initially negative. 
An ultrasound examination revealed thrombosis of both jugular internal veins, right axillary and subclavian veins. The TTE confirmed dilated evolution of PPCM, with further thrombi around the wire of the previously Implanted Cardioverter Defibrillator  (ICD). 
An immediate decision was made to replace AT and C protein deficiency with human AT solution concentrate (Kybernin� CSL Berhing GmbH , Marburg Germany)  and with C protein concentrate (Ceprotin�, Baxter Bio Science Glendale USA) 50 UI/kg every 24 hours, after an initial bolus of 100 UI/kg, in combination with fondaparinux 2.5 mg twice a day (Arixtra Sanofi-Synthelabo, Toulouse, France). 
After the failed therapy with dobutamine ev (6mcg/Kg/min), Levosimendan was also administered (0,1mcg/Kg/min) without any significant improvement.
After two weeks, the patient�s clinical condition rapidly deteriorated to cardiogenic shock, associated with an increase in lactate acidosis (7.7 mmol/l). IABP was quickly inserted at bedside and epinephrin was associated with a dobutamine infusion.
After the stop of Fondaparinux, Heparin infusion was starded to achieve activated partial thromboplastin time (aPTT) between 50-60 sec, while the replacement of AT and C protein was carried on. 
On the 7th day of IABP support, the patient had an arrhythmic storm treated with amiodarone, magnesium sulfate infusion and multiple cardioverte defibrillator shocks. 
The test for HIT was repeated for severe thrombocytopenia (PLTs 36 x 103 /uL). Total body Computed Tomography was performed to rule out thromboembolic complications.
The patient was intubated and, twelve hours after intubation, received an urgent heart transplant.
Suspecting HIT, a phosphorylcholine-coated circuit and a membrane oxygenator (Sorin Group Deuschland GmbH, Munich, Germany) were used for a cardiopulmonary bypass (CPB). Monitoring of anticoagulation was supported by both thromboelastometry (Rotem�, Tem International GmbH, Munich Germany) and Activated Clotting time (ACT). The anticoagulation was performed with an intravenous administration of heparin 25.000 UI (400 U/kg) , AT 1000 UI and concentrate C protein  2000 UI (30 UI/kg), to achieve ACT target of 500 sec. 
The weaning from CPB was sustained by isoprenaline (0.01 mcg"kg-1 "min-1 ), Adrenaline (0.1 mcg"kg-1"min-1) and  IABP  support.
During the hemostatic phase, protamine hydrochloride (250mg corresponding to 25.000 UI heparin antidote units) and six units of platelet concentrates were administered intravenously, with the guidance of Rotem� (decreased clot firmness in the INTEM and EXTEM assay, despite normal clot firmness in the FIBTEM assay).
Due to ongoing bleeding of the operative field, and despite heparin reversal and the optimization of surgical haemostasis and medical therapy, DDAVP (Minirin Parentera Ferring GmbH, Kiel, Germany) was administered at the dosage 0.3mcg/kg. Two units of packed red blood cells were transfused to maintain haemoglobin values at about 9.5 gr/dl.
At the end of surgery, the result of the preoperative HIT test was disclosed as positive. Anticoagulation for IABP was continued in the form of Fondaparinux (2.5 mg twice a day), as was the monitoring of AT, Coagulative C protein ,  S protein,  D Dimer, PT, aPTT and Fibrinogen values.
Adrenalin infusion was rapidly discontinued. Extubation was performed 24 hours after surgery, while IABP was removed after three days. 
The patient was discharged from ICU with oral anticoagulant therapy (warfarin) ten days after transplantation. AT, Coagulative C protein and PLT values were normalized without the need for replacement and the D Dimer values progressively decreased.

Discussion

A delicate physiological balance exists between fibrin formation and fibrinolysis. Alterations of the vessel wall, reduced blood flow and hypercoagulable state may promote the formation of thrombi. 
Pregnancy is an acquired risk factor for hypercoagulation. High levels of fibrinogen and factor VIII normally characterize it. Both increase the risk for venous and arterial thrombosis during pregnancy and puerperium.
Factor VIII and von Willebrand Factor (vWF) circulate in plasma in a tight non-covalent complex, whose levels are dependent on endothelial stimulation and blood group.
Indeed, blood groups A, and AB are associated with higher plasmatic levels of factor VIII, vWF and more frequent thrombotic events than blood group O. 1,2
Hypercoagulable state can also occur due to a deficiency of endogenous anticoagulant factors, such as C protein, which can cause a loss of Factor V inhibition.
Protein C deficiency can present itself as a rare autosomal recessive disorder, usually during the neonatal period, or it can be caused by increased consumption (disseminated intravascular coagulation, severe infection, acute venous thromboembolism) or decreased synthesis (hepatic dysfunction, therapy with vitamin K antagonist). 3
Our patient showed the coexistence of all these factors. She had blood group A, a high plasmatic value of Factor VIII associated with acquired C protein and AT deficiency. These deficits could be due to a combination of hepatic dysfunction and consumption for venous and cardiac thrombosis.
Despite the fact that thrombophilia screening resulted negative for significant alterations, the patient�s coagulative balance was destabilized towards pro-coagulation.
The therapeutic option was to replace C protein and AT in combination with anticoagulant therapy. Their doses were sufficient to maintain C Protein level and AT activity at about 60% and 100% respectively.  Fondaparinux, a synthetic pentasaccharide and a selective inhibitor of Factor Xa, was initially preferred for its effective and safe anthitrombotic action. 4,5 Its use was also required in postoperative anticoagulation, since Fondaparinux is non-reactive to HIT sera. 6
 The management of anticoagulation for CPB was performed using a combination of Heparin, AT and C protein bolus, without the need of additional heparin bolus. Tranexamic acid was not administered due to pre-existing thrombosis and due to the fact that there was no detection of hyperfibrinolysis with thromboelastometric assay. 7
The efficacy of C protein replacement was monitored in correlation with the decrease of the D Dimer values. 
Despite native heart surgical manipulation and HIT syndrome, at that moment unknown, no thromboembolic complication occurred.
This case regarding the use of C protein concentrate as an adjuvant anticoagulant for heart transplant required after PPCM complicated by HIT, venous and cardiac thrombosis associated with thrombophilic disorder. Given the rarity of C protein deficiency, it will be necessary to further explore this context.






References

1 G�rlinger K, Dirkman D, Hanke AA, et al. First line therapy with coagulation factor concentrates combined with point of care coagulation testing is associated with decreased allogenic blood transfusion in cardiovascular surgery. Anesthesiology 2011; 115(6):1179-91

2 Larsen T.B, Johnsen S.P, Gislum M, et al. ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population-based, nested case control study. J Thromb Haemost 2005; 3(2): 300-4

3 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated Factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21(5): 731-8

4 Goldenberg NA, Manco�Johnson MJ. Protein C Deficiency Haemophilia 2008; 14(6): 1214-21

5 Turpie AG, Gallus AS, Hoek JA. A pentasaccharide for the prevention for deep vein thrombosis after total hip replacement New Eng J Med; 344(9):619-25

6 Vullemenot A, Schiele F, Meneveau N, et al. Efficacy of Pentasaccharide, a pure factor Xa inhibitor as antithrombotic agent. A pilot study in the setting of coronary angioplasty Thromb Haemost 1999;81(2):214-20

7 Savi P, Chong BH, Greinacher A, et al. Effect of fondaparinux on platelet activation in the presence of heparin�dependent antibodies: a blinded comparative multicenter study with unfractioned heparin.  Blood 2005;105(1):139-44


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