(VII-VIII-4) Acute thromboembolic disease complicated with heparin induced thrombocytopenia type II in pregnant woman Leszek Drabik. MD, Agata Leśniak-Sobelga MD, PhD, Lidia Tomkiewicz-Pająk MD, PhD, Magdalena Kostkiewicz MD, PhD, Maria Olszowska MD, PhD, Prof. Piotr Podolec MD, PhD, Sylwia Wiśniowska –Śmiałek MD.

Background
Heparin induced thrombocytopenia type II (HIT-II) is immune-mediated disorder with life-threatening prothrombotic complications. HIT-II is caused by formation of antibodies which activate the platelets following heparin administration [1]. The incidence of HIT-II is lower in pregnant than in nonpregnant women [2].
Several features of the history and physical examination support a diagnosis of HIT-II [3]:
-fall in platelet count ≥50%, from highest platelet count after heparin exposure, in 10% of cases platelet count fall is 30-50%
-fall in platelet count begins 5-14 days after heparin exposure (≤48 hours in patients with previous heparin exposure within last 100 days)
– nadir platelet count ≥20x109/L in cases associated with thrombosis and disseminated intravascular coagulation
– venous or arterial thrombosis occurring ≥5 days after heparin exposure and up to 30 days after heparin cessation
– skin necrosis at subcutaneous heparin injection sites
– anaphylactoid reaction within 30 minutes after intravenous heparin bolus
– absence of alternative causes of thrombocytopenia such as infection, other medications known to cause thrombocytopenia, cardiopulmonary bypass within previous 96 hours etc.
– absence of petechiae and other significant bleeding
A clinical suspicion of HIT-II must be confirmed by detection of antibodies against platelet factor 4/heparin or antibodies that induce heparin-dependent platelet activation.
Treatment of HIT-II includes use of non heparin anticoagulants, such as factor IIa inhibitors (lepirudin, argatroban, bivalirudin), and factor Xa inhibitors (danaparoid, fondaparinux) [2]. There are limited data on treatment in pregnancy. The largest series of cases shows efficiency of danaparoid and fondaparinux. In the group of 83 patients with intolerance to heparins and acute or past thromboses, treated with danaparoid, 2 post cesarean deaths, 3 non-fatal major bleeds, 3 thrombo-embolic events were observed. Seven early miscarriages and 1 neonatal death were also reported [4]. In the group of pregnant women (n=10) with skin allergy to heparin treated with fondaparinux – no deaths, major bleeds and thrombo-embolic events were observed [5]. Between the 12th and 36th weeks of pregnancy and postpartum warfarin may be used after recovery of platelet counts [6].

Case presentation
A 31-year-old women, at 18th week of second pregnancy, was admitted to our centre for management of deep vein thrombosis (DVT) complicated with heparin induced thrombocytopenia type II (HIT II). At the age of 18 hormonal contraceptives had to be stopped due to calf pain, proximal DVT was exluded. The patients had a strong family history of miscarriages. Concomitant diseases included obesity, Gilbert’s syndrome and cholelithiasis. The patient was allergic to: iodine, NSAIDs, penicillin and cefuroxime.
Two months prior to admission the diagnosis of left iliofemoral DVT was made. Treatment included UFH for 4 days, nadroparin 10.000 U twice daily for 2 weeks and then enoxaparin 100 mg twice daily for 2 weeks. Despite anticoagulative treatment clinical deterioration due to thrombosis progression was observed. The patient presented with dyspnea and chest pain. No hypotension was observed. Laboratory analysis revealed marked thrombocytopenia 38×103/µl and high level of D-dimers 17800 mg/l (FEU). Due to high clinical probability of heparin induced thrombocytopenia, low-molecular weight heparin was discontinued and treatment with fondaparinux 7.5mg once a day was introduced. Two weeks later thrombosis of inferior vena cava and bilateral iliofemoral DVT were diagnosed. Deficiency of protein C, protein and antithrombin were exluded.
On admission, the patient complained of dyspnea during daily activities, cough and pre-syncopal epizodes. Current treatment included fondaparinux 7.5mg subcutaneously once a day, verapamil 40 mg twice a day, ferric sulfate once a day, folic acid once a day, metamizole twice a day and erythromycin lactobionate 15 mg/kg/day. Physical examination revealed no hypotension and cyanosis. Weight was 98 kg, height 178 cm, BMI 30.9 kg/m2 , BP 134/82 mmHg, HR 90 bpm. Lower limbs were tender, warm and swollen, without skin lesions. Condition of the fetus (16-17 weeks old), assessed by gynecological examination with fetal ultrasonography, was normal.
Laboratory and biochemical analysis showed: increased levels of the inflammatory biomarkers; D-dimers, mild normocytic anemia; normal platelet count; NT-proBNP level and troponin were within normal limits. Antibodies against platelet factor 4/heparin were present (GTI Diagnostics PF4 IgG, OD>0,4).
Resting ECG showed sinus rhythm with a heart rate of 90 beats/minute. The transthoracic echocardiography showed normal cardiac chamber dimensions, preserved biventricular systolic function, no evidence of thrombus.

Dose adjustment in renal or hepatic failure is required.

References
[1] Tanveer A.
Heparin induced thrombocytopenia-type 2
Asian J Transfus Sci. 2010 July; 4(2): 137.
[2] Fausett MB, Vogtlander M, Lee RM, et al.
Heparin-induced thrombocytopenia is rare in pregnancy.
Am J Obstet Gynecol. 2001 Jul;185(1):148-52.
[3] 2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia (HIT) American Society of Hematology
http://www.hematology.org/Practice/Guidelines/2934.aspx
[4] Magnani HN.
An analysis of clinical outcomes of 91 pregnancies in 83 women treated with danaparoid (Orgaran).
Thromb Res. 2010 Apr;125(4):297-302. Epub 2009 Aug 5.
[5] Knol HM, Schultinge L, Erwich JJ, Meijer K.
Fondaparinux as an alternative anticoagulant therapy during pregnancy.
J Thromb Haemost. 2010 Aug;8(8):1876-9. doi: 10.1111/j.1538-7836.2010.03926.x. Epub 2010 May 21.
[6] Lindhoff-Last E, Bauersachs R.
Heparin-induced thrombocytopenia-alternative anticoagulation in pregnancy and lactation.
Semin Thromb Hemost. 2002 Oct;28(5):439-46.
[7] www.fda.gov

Expert’s comments:(Written authorization required from each expert)

1. Prof. Anetta Undas, MD, PhD
I recommend anticoagulation therapy with fondaparinux 7.5mg subcutaneously once a day and dose adjustment of fondaparinux to anti-Xa level (standardization of coagulation analyzers to fondaparinux is required).
When therapeutic level of fondaparinux is maintained warfarin should be introduced. Therapy with warfarin to a target INR of 3.0 should be continued. When the desired INR has been maintained for 1-2 days fondaparinux may be discontinued. From 36th week of pregnancy switch to fondaparinux should be performed.

2. Andrzej Brzychczy, MD, PhD
Prophylactic IVC filter placement cannot be performed in this patient. I recommend anticoagulation therapy and graduated compression stockings.

3. Grzegorz Kopeć, MD, PhD
Expert’s signature in pregnant women with acute deep vein thrombosis low molecular weight
heparin is preferred over vitamin K antagonist. When compared with vit. K antagonists low molecular weight heparin is more effective in prevention of recurrent deep vein thrombosis and the postthrombotic syndrome without increasing the risk of major bleeding. Due to very high risk of deep vein thrombosis and relatively high rate of proximal thrombi in pregnant women anticoagulation should be continued throughout pregnancy and at least 6 weeks in the post partum period. The prevalence of heparin induced thrombocythopenia is low in pregnant women however when occurs withdrawal of low molecular weight heparin is required. It should be substituted with other anticoagulant and currently danaparoid is the agent of choice. When danaparoid is not available lepirudin, argatroban or fondaparinux can be used.

Expert’s conclusions:
The patient was qualified for conservative treatment and regular follow-up. Further investigations revealed a previously undiagnosed primary antiphospholipid syndrome. After introduction of warfarin no complications were observed.

Authors:
Leszek Drabik. MD¹, Agata Leśniak-Sobelga MD, PhD¹, Lidia Tomkiewicz-Pająk MD, PhD¹, Magdalena Kostkiewicz MD, PhD¹, Maria Olszowska MD, PhD¹, Prof. Piotr Podolec MD, PhD¹, Sylwia Wiśniowska –Śmiałek MD¹

Experts:
Prof. Anetta Undas MD, PhD²,Andrzej Brzychczy MD³, Grzegorz Kopeć MD, PhD.¹

¹Department of Cardiac and Vascular Disease in John Paul II Hospital, Institute of Cardiology, Faculty of Medicine, Jagiellonian University, Krakow, Poland.
²Department of Cardiac Surgery, Anesthesiology and Experimental Cardiology, Institute of Cardiology, Jagiellonian University Collegium Medicum, Krakow, Poland.
³Department of Cardiovascular Surgery and Transplantology Institute of Cardiology Jagiellonian University Collegium Medicum in John Paul II Hospital in Krakow.